CN1223650A - Piperidines and pyrrolidines - Google Patents
Piperidines and pyrrolidines Download PDFInfo
- Publication number
- CN1223650A CN1223650A CN 97193878 CN97193878A CN1223650A CN 1223650 A CN1223650 A CN 1223650A CN 97193878 CN97193878 CN 97193878 CN 97193878 A CN97193878 A CN 97193878A CN 1223650 A CN1223650 A CN 1223650A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- ethyl
- pyridyl
- piperidines
- Prior art date
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- Pending
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- 150000003235 pyrrolidines Chemical class 0.000 title abstract description 3
- 150000003053 piperidines Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 143
- 238000006243 chemical reaction Methods 0.000 claims description 135
- -1 hexanaphthene carboxylic acid Chemical class 0.000 claims description 116
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 230000005764 inhibitory process Effects 0.000 claims description 10
- 230000004048 modification Effects 0.000 claims description 10
- 238000012986 modification Methods 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 7
- 230000002349 favourable effect Effects 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 238000012545 processing Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 239000011737 fluorine Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 8
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- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- ORYOIBJWFDNIPD-UHFFFAOYSA-N diacetyl 2,3-dihydroxybutanedioate Chemical compound CC(=O)OC(=O)C(O)C(O)C(=O)OC(C)=O ORYOIBJWFDNIPD-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
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- 239000001087 glyceryl triacetate Substances 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
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- 150000002460 imidazoles Chemical class 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
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- 208000028867 ischemia Diseases 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- FZERHIULMFGESH-UHFFFAOYSA-N methylenecarboxanilide Natural products CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 1
- DHGUGEBXVGPRRD-UHFFFAOYSA-N n-(2,2-diethoxyethyl)aniline Chemical compound CCOC(OCC)CNC1=CC=CC=C1 DHGUGEBXVGPRRD-UHFFFAOYSA-N 0.000 description 1
- XZLXIUPFKGLCAG-UHFFFAOYSA-N n-[2-(4,4-diphenylpiperidin-1-yl)ethyl]-3-fluoroaniline Chemical compound FC1=CC=CC(NCCN2CCC(CC2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 XZLXIUPFKGLCAG-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
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- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- LTHCSWBWNVGEFE-UHFFFAOYSA-N octanamide Chemical class CCCCCCCC(N)=O LTHCSWBWNVGEFE-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- WWPITPSIWMXDPE-UHFFFAOYSA-N para-chloroamphetamine Chemical compound CC(N)CC1=CC=C(Cl)C=C1 WWPITPSIWMXDPE-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 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
- 229960003742 phenol Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer 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
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002804 pyramidal tract Anatomy 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
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- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 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 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
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- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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- 239000011782 vitamin Substances 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to novel piperidine and pyrrolidine derivatives of formula (I) in which R[1], R[2], R[3], k, l, m and n have the meanings indicated in Claim 1, and their salts, novel intermediates and processes for the preparation of the compounds according to the invention. The compounds of formula (I) act as 5-HT1A receptor antagonists and exhibit 5-HT reuptake-inhibiting actions and can be used for the production of medicaments.
Description
The present invention relates to formula I compound and salt thereof
R wherein
1For not replacing or by A, A-O-, OH, Hal, CN, NO
2, NH
2, Ph ,-O-SO
2A and/or-O-SO
2CF
3Single replacement, two replaces or trisubstd phenyls,
Do not replace or replace or dibasic 2-or 3-indyl by A, A-O-, OH, Hal and/or CN are single,
1,4-benzodioxan-5-or-6-base or
1-or 2-naphthyl, R
2Be phenyl or pyridyl, it is not substituted or replaces or two replacements R by A, A-O-, OH, Hal and/or CN are single
3Be H, A, A-O-, Ph, NHR
4Or NR
5R
6, R
4Be phenyl or pyridyl, it is not substituted or replaces or two replacements by A, A-O-, OH, Hal and/or CN are single, or for having the cycloalkyl of 3-10 carbon atom, R
5And R
6Together for having the alkylidene chain of 4,5 or 6 carbon atoms, A is the straight or branched alkyl with 1-10 carbon atom, it can be replaced by 1-5 F and/or Cl atom, or for having the cycloalkyl of 3-10 carbon atom, Hal is F, Cl, Br or I, and k and l are 0 or 1 independently of one another, and m is 0,1 or 2, and n is 1 or 2, and condition is k k=0 when being not equal to l and m=2.
Compound with similar structures can be known from various early stage publications and patent application.For example WO95/02592 has described the compound of following structure
Wherein R can be monocycle, dicyclo or heterocyclic group, and A can be a branching or sub-branched alkyl chain and heterocycle can not have two keys.Yet, in this application, A is only disclosed wherein for being thiophene, 1 by methyl substituted ethylidene and R, the compound of 4-benzodioxan, 4-indyl or methoxyphenyl ring.Corresponding compounds demonstrates 5-HT
1AReceptors bind.
Has 5-HT
1AThe bridged piperazine derivatives of antagonistic action for example is described among the WO95/33743.
The present invention is based on the novel cpd that discovery has useful performance, particularly those can be used to produce compound this purpose of medicine.
Have now found that formula I compound and salt thereof have useful especially pharmacological properties and has good tolerability, particularly, especially have 5-HT because they have effect to central nervous system
1AAntagonistic action, particularly 5-HT reuptake inhibition.
For having 5-HT simultaneously
1AThe compound of antagonistic action and 5-HT reuptake inhibition, can expect have good especially antidepressant, angst resistance effect and obsessional idea and behavior (OCD), eating disorder had favourable influence as voracity, tardive dyskinesia, dysacousis, age dependent form dysmnesia and psychosis.
Compound to WO95/02592 is not described the 5-HT reuptake inhibition.
The compounds of this invention is as 5-HT
1AThe activity of antagonist with and the 5-HT reuptake inhibition through test some representative formula I compound is confirmed.Pharmacological test data is compiled in the table I.
Formula I compound and physiologically acceptable acid salt thereof have useful especially pharmacological properties and good tolerability, particularly because of them central nervous system are had effect, especially 5-HT
1AAntagonistic action and 5-HT reuptake inhibition.They suppress tritium for combine (Cossery etc., European pharmacology magazine, 140 (1987) of 5-hydroxytryptamine receptor ligand with the hippocampus acceptor, 143-155) and suppress cynapse (synaptosomal) serotonin reuptake transporter (Sherman etc., life science, 23 (1978), 1863-1870).In addition, change at each brain region generation 5-HT cumulative (Seyfried etc., European pharmacology magazine, 160 (1989), 31-41).5-HT
1AAntagonistic action for example by the electricity of the guinea pig ileum that suppresses to cause by 8-OH-DPAT induce contraction disappearance and at external showing (Fozard and Kilbinger, Britain's pharmacology magazine, 86 (1985) 601P).In the isolated test (Exvivo), suppress 8-OH-DPAT the 5-HT cumulative is reduced (Seyfried etc., Europe pharmacology magazine, 160 (1989), 31-41) and in the test of ultrasonic sounding to the antagonism (DeVry of the effect of bringing out by 8-OH-DPAT, psychopharmacology, 121 (1995), 1-26) be used to illustrate 5-HT
1AAntagonistic action.The cynapse picked-up suppresses (Wong etc., the spirit neuropharmacology, 8 (1993), 23-33) with parachloroamphetamine antagonistic action (Fuller etc., pharmacology test treatment magazine (J.Pharmacol.Exp.Ther.) 212 (1980) 115-119) is used for showing that at isolated test serotonin reuptake transporter suppresses.Therefore formula I compound is applicable in for animals and human drugs of the dysfunction of treatment central nervous system and inflammation.They can be used for prevention and control cerebral infarction sequela (apoplexia cerebri) as apoplexy and cerebrum ischemia, also are used for the treatment of the outer motor side effect of pyramidal tract and the Parkinson disease of neural Depressant.Yet, they are particularly suitable for being used as the pharmaceutical active compounds of anxiolytic, thymoleptic, Antipsychotic drug or/and be used for favourable influence obsessional idea and behavior, somnopathy, tardive dyskinesia, dysacousis, age dependent form dysmnesia, eating disorder such as voracity, and/or sexual function disease.
Therefore, formula I compound and physiologically acceptable acid salt thereof can be with the pharmaceutical active compounds that acts on anxiolytic, thymoleptic, Antipsychotic drug, neural Depressant and/or antihypertensive drug, and be used for favourable influence obsessional idea and behavior, eating disorder such as voracity, tardive dyskinesia, dysacousis and age dependent form dysmnesia.
Therefore the present invention relates to formula I compound and physiologically acceptable acid salt thereof.
The invention particularly relates to the formula I compound and the salt thereof that are selected from following compound:
A) N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
B) N-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
C) N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
D) N-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
E) N-(2-(3-(1,4-benzodioxan-6-yl) tetramethyleneimine-1-yl) ethyl)-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
F) N-(2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl)-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
G) N-(2-(3-(7-methoxyl group-2-naphthyl) tetramethyleneimine-1-yl) ethyl)-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
H) R-(+)-N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
I) S-(-)-N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
J) N-(2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl)-N '-(3-fluorophenyl)-N-(2-pyridyl) urea;
K) N-cyclohexyl-N '-(2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl)-N '-(2-pyridyl) urea;
L) N-cyclohexyl-N '-(2-(3-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl)-N '-(2-pyridyl) urea;
M) N-(2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl)-N-(2-pyridyl)-N '-(4-trifluoromethyl) urea.
Formula I compound can be used as pharmaceutical active compounds in human and medicine for animals.They also can be used as the intermediate of preparation other drug active compound.
Therefore the present invention relates to formula I compound and preparation according to the method for the formula I compound of claim 1, it is characterized in that:
A) make formula II compound
R wherein
1, R
2, the implication that m and n have in the claim 1 to be given is reacted with formula III compound
R
3-CO-L (III) wherein L is the OH group of Cl, Br, I or free or reactive functional modification, and
R
3The implication that has in the claim 1 to be given, perhaps
B) make formula IV compound
R wherein
1With the implication that n has in the claim 1 to be given, react with formula V compound
Wherein L is the OH group of Cl, Br, I or free or reactive functional modification, and
R
2, R
3, m, k and the l implication that has in the claim 1 to be given, perhaps
C) in the reductive amination reaction, make formula VI compound
R wherein
2, R
3, m, k and the l implication that has in the claim 1 to be given, with the reaction of formula IV compound, perhaps
D) make formula VII compound
R wherein
2And R
3The implication that has in the claim 1 to be given is reacted with formula VIII compound
Wherein L is the OH group of Cl, Br, I or free or reactive functional modification, and
R
1, m and the n implication that has in the claim 1 to be given, perhaps
E) make the acid amides of formula VII, wherein R
2And R
3Have above-mentioned implication, with the reaction of formula IX compound,
R wherein
1, n and the m implication and the Q that have in the claim 1 and given be the OH group of Cl, Br, I or free or reactive functional modification, perhaps
F) make formula X compound
R wherein
1, R
3, m and the n implication that has in the claim 1 to be given, phenyl or pyridinyl derivatives reaction with suitable obtain formula I compound, the latter can at random be converted into another formula I compound, perhaps
G) in order to prepare wherein R
3Be NHR
4And R
4The formula I compound of the implication that has in the claim 1 to be given,
Make wherein R
1, R
2, m and the n implication that has in the claim 1 to be given formula II compound and the reaction of formula XI compound
R
3-N=C=O (XI) is R wherein
3The implication that has in the claim 1 to be given, and/or be by with acid treatment the basic cpd of formula I being converted into its a kind of salt.
Except as otherwise noted, the radicals R in the context
1, R
2, R
3, L, Q, k, l, m and n have implication shown in formula I, II, III, IV, V, VI, VII, VIII, IX, X and the XI.
The present invention relates to equally and has 5-HT
1AThe medicine of the formula I of antagonistic action and 5-HT reuptake inhibition and physiologically acceptable salt thereof.
The present invention relates to formula I compound, its enantiomorph and diastereomer and salt thereof according to claim 1.
For all groups that occur several times, A for example, their implication is separate.
Alkyl has 1-10, preferred 1,2,3,4,5 or 6 carbon atom.Therefore alkyl especially is for example methyl, also has ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the sec-butyl or the tertiary butyl also have amyl group in addition, 1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2, the 2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group, also have methyl fluoride, difluoromethyl, trifluoromethyl in addition, 1,1,1-three chloroethyls or pentafluoroethyl group.
A-O-especially is for example methoxyl group, oxyethyl group, propoxy-or butoxy.
Cycloalkyl especially is for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or 1-adamantyl.
Ph is a phenyl.
R
1For replacement, by A, A-O-, OH, Hal, CN, NO
2, NH
2, Ph ,-O-SO
2A or-O-SO
2-CF
3Single replacement, two replaces or three replacements, especially single the replacement or dibasic phenyl; 1-or 2-naphthyl or 2-or 3-indyl, they can be equally unsubstituted, singly replace, two replace or three replacements by A, A-O-, OH, Hal or CN, especially singly replace or two replace, and can also be 1,4-benzodioxan-5-or-the 6-base.
So R
1Be preferably for example 1-or 2-naphthyl, 2-or 3-indyl, 5-or 6-skatole-2-base, 5-or 6-skatole-3-base, 5-or 6-methoxyl group indoles-2-base, 5-or 6-methoxyl group indol-3-yl, 5-or 6-oxyindole-2-base, 5-or 6-oxyindole-3-base, 5-or 6-fluoro indole-2-base, 5-or 6-fluoro indole-3-base, 5-or 6-cyanoindole-2-base, 5-or 6-cyanoindole-3-base, phenyl, adjacent-, between-or right-tolyl, adjacent-, between-or right-trifluoromethyl, adjacent-, between-or right-methoxyphenyl, adjacent-, between-or right-hydroxy phenyl, adjacent-, between-or right-fluorophenyl, adjacent-, between-or right-chloro-phenyl-, adjacent-, between-or right-cyano-phenyl, 2-, 3-or 4-xenyl, adjacent-, between-or right-sulfonyloxy methyl oxygen base phenyl, adjacent-, between-or right-trifluoro-methanesulfonyl oxy phenyl, 1,4-benzodioxan-5-or-the 6-base, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-bromo-3-methoxyphenyl, 2-bromo-4-methoxyphenyl, 2-bromo-5-methoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-or 3, the 4-dimethoxy phenyl, 2,3-, 2,4-, 2,5-, 2,6-or 3,4-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-or 3, the 4-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-or 3, the 4-aminomethyl phenyl also has 3 in addition, 4,5-three chloro-or 3,4, the 5-trimethoxyphenyl.
R
2Be phenyl or pyridyl, it is not substituted or by A, A-O-, OH, Hal or CN are single to be replaced or two replacements, and be preferably for example phenyl, adjacent-, between-or right-tolyl, adjacent-, between-or right-trifluoromethyl, adjacent-, between-or right-methoxyphenyl, adjacent-, between-or right-hydroxy phenyl, adjacent-, between-or right-fluorophenyl, adjacent-, between-or right-chloro-phenyl-, adjacent-, between-or right-cyano-phenyl, adjacent-, between-or right-ethylphenyl, 2-, 3-or 4-pyridyl, 3-, 4-, 5-or 6-fluorine pyridine-2-base, 2-or 3-fluorine pyridin-4-yl, 3-, 4-, 5-or 6-5-flumethiazine-2-base.
R
3Be preferably for example H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the sec-butyl or the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, tert.-butoxy also has amyl group in addition, hexyl, trifluoromethyl, pentafluoroethyl group, cyclopentyl, cyclohexyl, 1-adamantyl, anilino, adjacent-, between-or right-toluino, adjacent-, between-or right-trifluoromethylbenzene amido, adjacent-, between-or right-anisole amido, adjacent-, between-or right-hydroxybenzene amido, adjacent-, between-or right-fluoroanilino, adjacent-, between-or right-chloroanilino, adjacent-, between-or right-cyano-aniline base, adjacent-, between-or right-ethylbenzene amido, 2-, 3-or 4-pyridinylamino, 3-, 4-, 5-or 6-fluorine pyridine-2-base is amino, 2-or 3-fluorine pyridin-4-yl amino, cyclopentyl amino, cyclohexyl amino or 1-adamantyl amino.R
3Also be preferably tetramethyleneimine-1-base, piperidino or 1-a word used for translation heptane base (azepanyl).
R
4Be phenyl or pyridyl, it is not substituted or by A, A-O-, OH, Hal or CN are single to be replaced or two replacements, also can be for having the cycloalkyl of 3-10 carbon atom, be preferably for example phenyl, adjacent-, between-or right-tolyl, adjacent-, between-or right-trifluoromethyl, adjacent-, between-or right-methoxyphenyl, adjacent-, between-or right-hydroxy phenyl, adjacent-, between-or right-fluorophenyl, adjacent-, between-or right-chloro-phenyl-, adjacent-, between-or right-cyano-phenyl, adjacent-, between-or right-ethylphenyl, 2-, 3-or 4-pyridyl, 3-, 4-, 5-or 6-fluorine pyridine-2-base, 2-or 3-fluorine pyridin-4-yl, cyclopentyl, cyclohexyl or 1-adamantyl.
For whole invention, the group that is occurred several times can be identical or different, and is promptly separate.
Therefore, the invention particularly relates to those formula I compounds that at least one described group wherein has one of above-mentioned preferred meaning.Some preferred compound can be represented by following inferior formula I a-I h, these inferior formulas corresponding to the formula I and wherein not in greater detail group have implication shown in the formula I, but wherein in I a, k is 0,
L is 1,
M be 2 and
N is 1 or 2; In I b, R
3Be H,
K is 1,
L be 0 and
M is 1; In I c, R
3Be H,
K is 0,
L be 0 and
M is 2; In I d, R
3For having the cycloalkyl of 3-10 carbon atom,
A is the straight or branched alkyl with 1-6 carbon atom, and it can replace with 1-5 F and/or Cl atom,
K is 0,
L is 1,
M be 2 and
N is 1 or 2; In I e, R
3Be A-O-,
A is the straight or branched alkyl with 1-6 carbon atom, and it can be replaced by 1-5 F and/or Cl atom,
K is 0,
L is 1,
M be 2 and
N is 1 or 2; In I f, R
3Be NHR
4Or NR
5R
6, and
A is the straight or branched alkyl with 1-6 carbon atom, and it can be replaced by 1-5 F and/or Cl atom; In I g, R
1For by methoxyl group, F, Cl, Br, OH, CN, Ph ,-O-SO
2CH
3Or-OSO
2CF
3Single replacement or dibasic phenyl, or be by F and/or mono-substituted 2-of CN or 3-indyl, 1,4-benzodioxan-5-or-6-base or 1-or 2-naphthyl,
R
2Be phenyl or 2-pyridyl, it replaces by F is single,
R
3For having the cycloalkyl of 5 or 6 carbon atoms, A-O-, NHR
4Or NR
5R
6,
R
4Be phenyl or pyridyl, it replaces by A, A-O-, Hal or CN are single, or is to have the cycloalkyl of 5 or 6 carbon atoms,
K is 0,
L is 1,
M be 2 and
N is 1 or 2; In I h, R
1For by methoxyl group, F, Cl, Br, OH, CN, Ph ,-O-SO
2CH
3Or-O-SO
2CF
3The single replacement or dibasic phenyl, by F and/or mono-substituted 2-of CN or 3-indyl,
1,4-benzodioxan-5-or-6-base or
1-or 2-naphthyl,
R
2For by F or the mono-substituted phenyl of A,
R
3For having the cycloalkyl of 5 or 6 carbon atoms, A-O-, NHR
4Or NR
5R
6,
R
4Be phenyl or pyridyl, it replaces by A, A-O-, Hal or CN are single, or is to have the cycloalkyl of 5 or 6 carbon atoms,
R5 and R6 are the alkylidene chain with 4,5 or 6 carbon atoms together,
K is 0,
L is 1,
M be 2 and
N is 1 or 2.
The present invention also relates in particular to wherein R
3=H, k=1, the formula I compound of l=0 and m=1 according to claim 1.Particularly, these compounds are selected from as follows:
2-(4-(6-fluoro indole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(1-naphthyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(2-naphthyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(4-(5-fluoro indole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide
2-(4-(5-cyanoindole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide
2-(4-(6-cyanoindole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(1-naphthyl) piperidines-1-yl)-N-(2-pyridyl) ethanamide and
2-(3-(2-naphthyl) piperidines-1-yl)-N-(2-pyridyl) ethanamide.
These compounds also are suitable for use as the intermediate of preparation formula I compound of the present invention.
Formula I compound with and prepare used initial substance also can be by known method preparation itself, as document (for example at classic such as Houben-Weyl, organic chemistry method (Methoden der organischen Chemie), Georg-Thieme-Verlag, Stuttgart) method described in is promptly known and be suitable under the reaction conditions of described reaction.In this case can also use itself is known improve one's methods, but do not make more detailed description here.
Q in L in formula III, V and the VIII compound or the formula IX compound is the OH group of Cl, Br, I or free or reactive esterification.
If L or Q are the OH group of reactive esterification, then be preferably the trichlorine methoxyl group, alkoxyl group such as methoxyl group, oxyethyl group, propoxy-or butoxy, also have phenoxy group, have the alkylsulfonyloxy (preferred mesyloxy) of 1-6 carbon atom or have the aryl-sulfonyl oxygen (preferably phenyl sulfonyloxy or tolysulfonyl oxygen base, 2-naphthalene sulfonyl oxygen base in addition) of 6-10 carbon atom.
If desired, initial substance also can form on the spot, thereby does not separate them from reaction mixture, but further reacts immediately, obtains formula I compound.
On the other hand, can progressively carry out this reaction.
Formula I compound preferably can obtain by making the reaction of formula II compound and formula III compound.
The initial substance of formula II and III is known in some cases.If they are unknown, then can be by known method preparation itself.
The suitable derivative example that is used for the formula III compound of N-acylations is an acyl halide; preferred chloride of acid; trinitride; the acid anhydride class; imidazoles thing (imidazolide can for example be obtained by carbonyl dimidazoles), activatory ester or O-acylurea; by suitable carboxylic imide such as dialkyl group carbodiimide, particularly the cyclohexyl carbodiimide obtains.Before carrying out this reaction, may must make other amino that contained in the formula II compound not participate in acylation reaction by introducing suitable blocking group.
This reaction is usually in inert solvent, carry out in the presence of sour binding reagents, the acid binding reagents is preferably oxyhydroxide, carbonate or the supercarbonate of basic metal or alkaline-earth metal, or the another kind of salt of weak acid of basic metal or alkaline-earth metal, the salt of weak acid of preferred potassium, sodium, calcium or caesium.The adding of organic bases such as triethylamine, xylidine, pyridine or quinoline or excessive formula II acid amides component or formula III alkyl derivative may also be favourable.Reaction times depends on that used condition is a several minutes to 14 day, and temperature of reaction is about 0 ℃ to 150 ℃, is generally 20 ℃ to 130 ℃.
Suitable inert solvent for example is hydro carbons such as hexane, sherwood oil, benzene, toluene or dimethylbenzene; Chlorinated hydrocarbons such as trieline, 1,2-ethylene dichloride, tetracol phenixin, chloroform or methylene dichloride; Alcohols such as methyl alcohol, ethanol, Virahol, n-propyl alcohol, the propyl carbinol or the trimethyl carbinol; Ethers such as ether, diisopropyl ether, tetrahydrofuran (THF) (THF) Huo diox; Gylcol ether such as ethylene glycol monomethyl ether or single ether (methyl glycol or ethyl glycol), glycol dimethyl ether (diglyme); Ketone such as acetone or butanone; Amides such as ethanamide, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF); Nitrile such as acetonitrile; Sulfoxide class such as methyl-sulphoxide (DMSO); Dithiocarbonic anhydride; Carboxylic acid such as formic acid or acetate; Nitro-compound such as Nitromethane 99Min. or oil of mirbane; The mixture of ester class such as ethyl acetate or above-mentioned solvent.
Term " amino protecting group " is normally known and relate to and be suitable for protection (sealing) amino and make its group that chemical reaction does not take place, but this group is easy to remove carry out required chemical reaction on the another location of this molecule after.The typical case of this class group particularly unsubstituted or acyl group, the aryl (for example dinitrophenyl (DNP)), aralkoxy methyl (for example benzyloxymethyl (BOM)) or the aralkyl (for example benzyl, 4-nitrobenzyl, trityl) that replace.Because remove this amino protecting group afterwards in required reaction (or reaction sequence), its character and size are not crucial; Yet, preferably have those of 1-20, a particularly 1-8 carbon atom.The term here " acyl group " should be with the wideest meaning interpretation.It comprises derived from the acyl group, particularly carbalkoxy of aliphatic series, araliphatic, aromatics or heterocycle family carboxylic acid or sulfonic acid, aryloxy carbonyl and especially aralkoxycarbonyl.The example of this class acyl group is alkanoyl such as ethanoyl, propionyl, butyryl radicals; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl (tolyl); Aryloxy alkanoyl such as phenoxy group ethanoyl; Carbalkoxy such as methoxycarbonyl, ethoxycarbonyl; 2,2,2-trichloro-ethoxycarbonyl, the different third oxygen carbonyl, tertbutyloxycarbonyl (BOC), 2-iodo ethoxycarbonyl; Aralkoxycarbonyl such as carbobenzoxy-(Cbz) (CBZ), 4-methoxyl group benzyloxy carbonyl and 9-fluorenylmethyloxycarbonyl (FMOC).
Preferred amino protecting group is BOC, DNP and BOM, also has CBZ, benzyl and ethanoyl in addition.The key factor of selecting used protecting group be after real reaction once more selectivity remove its possibility.
The amine of formula II can be by known method preparation itself, for example as standard reductive alkylation formula IV compound as described in the EP512755A2.
Formula I compound can also preferably be obtained by formula IV compound and the reaction of formula V compound.
The initial substance of formula IV and V is known in some cases.If they are unknown, then can prepare with known method itself.This is reflected in the solvent and carries out under said temperature.
Formula I compound is also preferably obtained by the reductive amination reaction of formula IV compound and formula VI compound.
The initial substance of formula IV and VI is known in some cases.If they are unknown, then can prepare with known method itself.
Reductive amination can be at reductive agent such as NaBH
3CN and NaBH (OAc)
3Carry out under existing.As I=0 and R
3During for H, be recommended in reductive amination and substitute R with amino protecting group before
3, preferably use tertbutyloxycarbonyl, to protect the amino attack that is not subjected to reductive agent.After taking place, the reductive amination reaction can remove blocking group once more with the known simple method of one skilled in the art.For example, if blocking group is a tertbutyloxycarbonyl, then can remove by handling with trifluoroacetic acid or in dilute hydrochloric acid.
The formula I compound preferably reaction of through type VII compound and formula VIII compound obtains.
The initial substance of formula VII and VIII is known in some cases.If they are unknown, then can be by known method preparation itself.This is reflected in the solvent and carries out under said temperature.
In the other method of preparation The compounds of this invention, make wherein R
2And R
3Have the formula VII acid amides of above-mentioned implication and R wherein
1, n and m has above-mentioned implication and leavings group Q is preferably halogen, for example bromine, or ester, for example formula IX alkylating reagent of tosylate or triflate reaction.
The initial substance of formula VII and IX is known in some cases.If they are unknown, then can prepare with known method itself.This is reflected in the solvent and carries out under said temperature.
The other method of preparation The compounds of this invention is to make wherein R
1, R
3, m and n have the formula X compound of given implication and suitable phenyl or pyridinyl derivatives reaction.Suitable those are the suitable fluorine substitution compounds that for example can be used for this reaction in the presence of non-nucleophilicity highly basic such as di-isopropyl lithamide.In order to prepare wherein R
2Be the formula I compound of 2-pyridyl, preferably make the reaction of formula X compound and 2-fluorine pyridine N-oxides, in the presence of appropriate reductant such as phosphorus trichloride, be reduced to the 2-pyridinyl compounds of required formula I then.
Prepare wherein R
3Be NHR
4The other method of formula I compound be the reaction of formula II compound and formula XI compound.The initial substance of formula XI is known in some cases.If they are unknown, then can be by known method preparation itself.
Further possible is with the radicals R in the formula I compound
1, R
2And/or R
4Be converted into another radicals R
1, R
2And/or R
4, for example, cyan-hydrolysis is become the COOH group or for example makes the ether fracture by the aromatics methoxyl group being converted into corresponding hydroxy derivatives by nitroreduction is amino (for example carrying out hydrogenation in inert solvent such as methyl alcohol or ethanol on Raney or Pd/C).
The alkali of formula I can use acid to be converted into associating acid salt, for example reacts in inert solvent such as ethanol by equivalent alkali and acid, then evaporation.For this reaction, possible acid is especially for producing those acid of physiologically acceptable salt.Therefore can use mineral acid, as sulfuric acid, nitric acid, haloid acid example hydrochloric acid or Hydrogen bromide, phosphoric acid such as ortho-phosphoric acid, thionamic acid, also has organic acid, especially aliphatic, alicyclic, araliphatic, aromatics or heterocycle family monocarboxylic acid or polycarboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetate, propionic acid, PIVALIC ACID CRUDE (25), diethylacetic acid, propanedioic acid, succsinic acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, methylsulfonic acid or ethyl sulfonic acid, ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, naphthalene list sulfonic acid and naphthalene disulfonic acid and lauryl sulfate.The salt that forms with unacceptable acid on the physiology, picrate for example can be used for the separation and/or the purifying of formula I compound.
On the other hand, formula I compound can be converted into corresponding metal salt, especially an alkali metal salt or alkaline earth salt with alkali (for example oxyhydroxide of sodium or potassium or carbonate), or is converted into corresponding ammonium salt.
Formula I compound of the present invention can be a chirality because of its molecular structure, therefore two kinds of enantiomeric forms or two or more diastereomer forms can occur.Owing to have one or more chiral centres, they can racemic forms or exist with the optically active form.
Because the racemic modification of The compounds of this invention or the pharmaceutical activity of steric isomer may be different, thereby it is desirable to use diastereomer or enantiomorph.In these cases, can by the known chemistry of those skilled in the art or physical method with final product or even intermediate be split as the mapping compound or be directly used in synthetic in.
Under the racemic amines situation, by forming diastereomer by mixture with the reaction of optically active resolution reagent.Suitable resolution reagent for example is optically active acid, as R and S type tartrate, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid, lactic acid, the suitably amino acid (as N-benzoyl proline(Pro) or N-benzene sulfonyl proline(Pro)) or the various optically active camphorsulfonic acid of N-protected.It also is favourable by optically active resolution reagent (for example other derivatives or the chirality deutero-methacrylate polymers of dinitrobenzoyl phenylglycocoll, cellulosic triacetate or the carbohydrate that links to each other with silica gel) enantiomorph being carried out that chromatogram splits.The eluent that is applicable to this purpose is moisture or pure property solvent mixture such as hexane/isopropyl alcohol/acetonitrile, and for example its ratio is 82: 15: 3.
Under the racemic outside situation, can advantageously use the alkali of optically active, for example R and S type 1-phenyl-ethyl amine, 1-naphthyl ethamine, dihydroabietic acid's base amine, cinchonine or cinchovatin.
But, under given conditions, even can also in building-up process, use the pure intermediate of suitable enantiomer ratios for preparing by one of aforesaid method.In this case, in further synthesizing, kept chirality.As under the situation of racemate (for example 4-(2-naphthyl)-2-oxo-pyrrolidine-3-carboxylicesters), these intermediates also can advantageously fragment into enantiomorph by the enantioselectivity enzymatically hydrolyse in the aqueous solution.The mapping ester can hydrolysis obtain mapping acid.Mapping acid or non-mapping acid can decarboxylation obtain corresponding intermediate enantiomer (for example corresponding pyrrolidone).The suitable enzymes that is used for the ester fracture is lipase (for example lipase of pseudomonas cepacia) and esterase.Particularly advantageous situation is the alpha-position of chiral centre at ester group.In this case, can make undesirable enantiomorph racemization, and therefore carry out new racemic modification fractionation through enolization.
The salt such as the picrate that form with unacceptable acid on the physiology can be used for separating and/or purifying of formula I compound.
The 5-HT of some representative formula I compound
1AThe test-results of receptors bind and 5-HT reuptake inhibition is compiled in the following table I.For to tritium for the inhibition of part and hippocampus serotonin-1A receptors bind (method and Cossery's etc. is similar) and for the inhibition of cynapse serotonin reuptake transporter (method and Sherman's etc. is similar) is shown and suppresses constant IC
50(concentration, nmol/l).
The table I
The IC of representative formula I compound
50(concentration, nmol/l), the method that is similar to people such as people such as Cossery or Sherman obtains value, and the fusing point that records (m.p.).
| R 1 | R 2 | R 3 | ?n | Salt | M.p.[℃] | ????IC 50?5- ????HT 1AIn conjunction with | IC 505-HT re-uptake suppresses |
| (1) | (A) | (a) | 1 1) | Oxalate 3) | ????173-176 | ?????9 | ????1 |
| (2) | (A) | (b) | 2 2) | ??????159 | ????100 | ????80 | |
| (1) | (A) | (a) | 1 1) | Oxalate | ????183-185 | ?????3 | ????20 |
| (1) | (A) | (a) | 1 1) | Oxalate 5) | ????174-176 | ?????2 | ????20 |
| (1) | (A) | (a) | 2 4) | Oxalate | ????150-155 | ????200 | ????30 |
| (3) | (A) | (a) | 2 2) | ?????? 6) | ????100 | ????50 | |
| (2) | (A) | (a) | 2 2) | Oxalate | ????182-185 | ?????30 | ????50 |
| (1) | (B) | (c) | 1 1) | Oxalate | ????107-110 | ????400 | ????50 |
| (2) | (C) | (b) | 2 2) | ??????188 | ????100 | ????70 | |
| (4) | (A) | (a) | 1 1) | Oxalate | ????122-125 | ?????4 | ????90 |
(1)=2-naphthyl (2)=6-fluoro indole-3-base
(3)=5-fluoro indole-3-base (4)=7-methoxynaphthalene-2-base
(A)=2-pyridyl (B)=4-fluorophenyl
(C)=the 2,4 difluorobenzene base
(a)=cyclohexyl (b)=NH-cyclohexyl (c)=1-adamantyl
1)3-R
1-tetramethyleneimine-1-based compound
2)4-R
1-piperidines-1-based compound
3)(S)-(-)-enantiomorph
4)3-R
1-piperidines-1-based compound
5)(R)-(+)-enantiomorph
6)R
f0.39 (CH
2Cl
2/ methyl alcohol 9: 1)
Pharmacological datum has confirmed the 5-HT of formula I compound of the present invention
1AReceptors bind and to the restraining effect of serotonin reuptake transporter.
The invention still further relates to the purposes that the physiologically acceptable salt of formula I compound and/or its is produced pharmaceutical preparation, especially in mode non-chemically.In this, they can make suitable formulation with at least a solid, liquid and/or semiliquid vehicle or auxiliary agent and suitable and one or more other active compounds combinations.
The invention still further relates to the pharmaceutical preparation that comprises at least a formula I compound and/or its a kind of physiologically acceptable salt.
These preparations can be as the medicine in people's medicine or the veterinary drug.Possible vehicle is the organic or inorganic thing, they be suitable for intestines portion (as oral) or administered parenterally or local application and not with these compounds reaction, for example water, vegetables oil, benzylalcohol, aklylene glycol, polyoxyethylene glycol, triacetin, gelatin, carbohydrate such as lactose or starch, Magnesium Stearate, talcum and Vaseline.Tablet, pill, coated tablet, capsule, powder, particle, syrup, juice or dropping liquid are particularly useful for oral administration, suppository can be used for rectal administration, solution, preferred oiliness or the aqueous solution, also have suspension, emulsion or implant to be used for administered parenterally in addition, and ointment, creme or powder are used for local application.The compounds of this invention also can freeze-drying and the obtained freeze-drying thing is used for for example producing injection formulations.Can sterilize and/or can contain other active compound of auxiliary agent such as lubricant, sanitas, stablizer and/or wetting agent, emulsifying agent, the salt that influences osmotic pressure, buffer substance, tinting material, seasonings and/or one or more, for example one or more VITAMIN above-mentioned preparation.
Formula I compound of the present invention is similar to other commercial preparation that become known for described indication (as Mi Paming, fluoxetine, clomipramine) and administration usually, and preferred dose is the 0.1mg-500mg/ dose unit, particularly the 5-300mg/ dose unit.Per daily dose is preferably about 0.01-250mg/kg body weight, particularly 0.02-100mg/kg body weight.
In this case, material of the present invention is general preferred with about 1-500mg/ dose unit, the particularly dosed administration of 5-100mg/ dose unit.The preferably about 0.02-10mg/kg body weight of per daily dose.But each patient's concrete dosage depends on various factors, as the severity of the related specified disease of effectiveness, age, body weight, common healthy state, sex, diet, administration time and mode, discharge rate, drug regimen and the treatment of used particular compound.The preferred oral administration.
In the context, all temperature are with a ℃ expression.In the following embodiments, " conventional processing " refers to: if desired, add entry, if need, according to the composition of final product mixture being adjusted to pH value is 2-10, and with ethyl acetate or dichloromethane extraction, separate organic phase, with dried over sodium sulfate and evaporation, resistates is by chromatography and purifying on silica gel, also can separating isomerism body as described below and/or by crystallization purifying.Rf value on silica gel; Elutriant: ethyl acetate/methanol 9: 1.Mass spectrum: EI (electron impact ionization): M
+
FAB (fast atom bombardment): (M+H)
+
The given concrete specific rotation of activity of optically active compounds is measured the solution of free alkali in all cases.Embodiment 1a)
20.4g (0.12mol) 4-(6-fluoro indole-3-yl) piperidines, 26.16g (0.12mol) N-2-(1-chloro acetylamino) pyridine (can obtain by 2-aminopyridine and chloro-acetyl chloride reaction) and 8.3g salt of wormwood were stirred 2 hours in 100 ℃ in 250ml DMF, steam then and remove DMF and also handle this mixture in the usual way.
Output: 20.4g2-(4-(6-fluoro indole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide (theoretical value 48%).
Obtain following compounds similarly:
2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide;
2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(1-naphthyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(3-(2-naphthyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-(4-(5-fluoro indole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide
2-(4-(5-cyanoindole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide
2-(4-(6-cyanoindole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide
2-(4-(1-naphthyl) piperidines-1-yl)-N-(2-pyridyl) ethanamide;
2-(4-(2-naphthyl) piperidines-1-yl)-N-(2-pyridyl) ethanamide;
(R)-(+)-and 2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide, α
D 20(+) 12.6 ° (c1.0, methyl alcohol);
(S)-(-)-and 2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide, α
D 20(-) 12.2 ° (c1.0, methyl alcohol);
2-(3-(4-methoxyphenyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide, R
f0.67 (CH
2Cl
2/ methyl alcohol 19: 1).
Similarly, by 2-chloro-N-(4-fluorophenyl) ethanamide
Obtain with the reaction of 4-(6-fluoro indole-3-yl) piperidines
2-(4-(6-fluoro indole-3-yl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 3-(6-fluoro indole-3-yl) tetramethyleneimine
2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 3-(5-fluoro indole-3-yl) tetramethyleneimine
2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 3-(5-cyanoindole-3-yl) tetramethyleneimine
2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 3-(6-cyanoindole-3-yl) tetramethyleneimine
2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 3-(1-naphthyl) tetramethyleneimine
2-(3-(1-naphthyl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 3-(2-naphthyl) tetramethyleneimine
2-(3-(2-naphthyl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide, R
f(0.21 n-hexane/ethyl acetate 2: 1);
Obtain with the reaction of 4-(5-fluoro indole-3-yl) piperidines
2-(4-(5-fluoro indole-3-yl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 4-(5-cyanoindole-3-yl) piperidines
2-(4-(5-cyanoindole-3-yl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 4-(6-cyanoindole-3-yl) piperidines
2-(4-(6-cyanoindole-3-yl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide;
Obtain with the reaction of 4-(1-naphthyl) piperidines
2-(4-(1-naphthyl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide, F.112-116 ℃;
Obtain with the reaction of 4-(2-naphthyl) piperidines
2-(4-(2-naphthyl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide; B)
20g2-(4-(6-fluoro indole-3-yl) piperidines-1-yl)-N-(2-pyridyl) ethanamide is dissolved in the 400ml anhydrous tetrahydro furan.At room temperature drip two (methoxy ethoxy) aluminium sodium (Vitride of 20ml hydrogenation then
).Stir after 2 hours, drip 10ml Vitride once more
Again mixture was stirred 2 hours.Add entry, the precipitation that suction strainer forms.Concentrated mother liquor.Resistates is dissolved in HCl and handles this mixture with usual manner.
Output: 17g2-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino } pyridine
Similarly,
Obtain by (R)-(+)-2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
(R)-(+)-and 2-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine, α
D 20(+) 11.8 ° (c1.0, methyl alcohol);
Obtain by (S)-(-)-2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
(S)-(-)-and 2-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine, α
D 20(-) 13.0 ° (c1.0, methyl alcohol);
Obtain by 2-(4-(6-fluoro indole-3-yl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino }-the 4-fluorobenzene;
Obtain by 2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethylamino }-the 4-fluorobenzene;
Obtain by 2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethylamino }-the 4-fluorobenzene;
Obtain by 2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino }-the 4-fluorobenzene;
Obtain by 2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino }-the 4-fluorobenzene;
Obtain by 2-(3-(1-naphthyl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(3-(1-naphthyl) tetramethyleneimine-1-yl) ethylamino }-the 4-fluorobenzene;
By 2-(3-(2-naphthyl) tetramethyleneimine-1-yl)-N-(4-fluorophenyl) ethanamide (R
f(0.21 n-hexane/ethyl acetate 2: 1)) obtain
2-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethylamino }-the 4-fluorobenzene, R
f0.39 (CH
2Cl
2/ methyl alcohol 45: 1);
Obtain by 2-(4-(5-fluoro indole-3-yl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethylamino }-the 4-fluorobenzene;
Obtain by 2-(4-(5-cyanoindole-3-yl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(4-(5-cyanoindole-3-yl) piperidines-1-yl) ethylamino }-the 4-fluorobenzene;
Obtain by 2-(4-(6-cyanoindole-3-yl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(4-(6-cyanoindole-3-yl) piperidines-1-yl) ethylamino }-the 4-fluorobenzene;
Obtain by 2-(4-(1-naphthyl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(4-(1-naphthyl) piperidines-1-yl) ethylamino }-the 4-fluorobenzene, R
f0.44 (CH
2Cl
2/ methyl alcohol 30: 1);
Obtain by 2-(4-(2-naphthyl) piperidines-1-yl)-N-(4-fluorophenyl) ethanamide
2-{2-(4-(2-naphthyl) piperidines-1-yl) ethylamino }-the 4-fluorobenzene.
Similarly, obtain by 2-(3-(3-fluoroform sulphonyl oxygen phenyl) tetramethyleneimine-1-yl)-N-(2-pyridyl) ethanamide
2-{2-(3-(3-fluoroform sulphonyl oxygen phenyl) tetramethyleneimine-1-yl) ethylamino } pyridine, R
f0.51 (CH
2Cl
2/ methyl alcohol 9: 1).c)
At first with 1.02g (0.003mol) 2-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino } pyridine and 0.3g (0.003mol) triethylamine introduce in the 20ml methylene dichloride.Under agitation drip 0.44g (0.003mol) the hexanaphthene carbonyl chloride (" A ") that is dissolved in the 5ml methylene dichloride.Stirring at room reaction mixture 2 hours is also handled with usual manner.Output: 0.5gN-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, hydrochloride, m.p.201 ℃.
Similarly, obtain following compounds:
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.182-185 ℃.
Similarly, by " A "
With 2-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(indoles-2-yl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(indoles-2-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides; M.p.192-195 ℃;
With 2-{2-(3-(2-methoxyphenyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.153-157 ℃;
With 2-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
With 2-{2-(4-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(4-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides; Fumarate, m.p.198-200 ℃;
With 2-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.203-205 ℃;
With 2-{2-(3-(2-naphthyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(2-naphthyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, m.p.150-155 ℃;
With 2-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.158-162 ℃;
With 2-{2-(3-(1-naphthyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(1-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.160-164 ℃;
With 2-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.183-185 ℃;
With 2-{2-(3-(1-methoxyl group-2-naphthyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(1-methoxyl group-2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.183-186 ℃;
With 2-{2-(3-(1,4-benzodioxan-6-yl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(1,4-benzodioxan-6-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.156-160 ℃;
With 2-{2-(3-(7-methoxyl group-2-naphthyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(7-methoxyl group-2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.122-125 ℃;
With (R)-(+)-2-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
R-(+)-N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.174-176 ℃, α
20 D(+) 19 ° of (c0.99, CHCl
3);
With (S)-(-)-2-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
S-(-)-N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.173-176 ℃, α
20 D(-) 19.7 ° of (c1.05, CHCl
3);
With 2-{2-(4-(4-methoxyphenyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(4-(4-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(4-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine, R
f0.13 (CH
2Cl
2/ MeOH=19: 1), reaction obtains
N-{2-(3-(4-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, m.p.151-154 ℃;
Ether fracture by this compound obtains
N-{2-(3-(4-hydroxy phenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, m.p.186-188 ℃;
With 2-{2-(3-(3-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine, R
f0.28 (CH
2Cl
2/ MeOH=19: 1), reaction obtains
N-{2-(3-(3-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, m.p.159-161 ℃;
With 2-{2-(4-(4-methoxyl group-3-bromophenyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(4-(4-methoxyl group-3-bromophenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(4-methoxyl group-3-bromophenyl) tetramethyleneimine-1-yl) ethylamino } pyridine, R
f0.32 (CH
2Cl
2/ MeOH=19: 1), reaction obtains
N-{2-(3-(4-methoxyl group-3-bromophenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides; M.p.95-102 ℃;
With (R)-(+)-2-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
R-(+)-N-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, m.p.158-161 ℃, 6.3 ° of α 20D (+) (c1.0, methyl alcohol);
With (S)-(-)-2-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
S-(-)-N-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2 pyridyl) hexanaphthene carboxylic acid amides, m.p.157-160 ℃, 5.8 ° of α 20D (-) (c1.0, methyl alcohol);
With 2-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(6-fluoro indole-3 base) tetramethyleneimine-1 base) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) cyclohexane carboxylic acid amides;
With 2-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(1-naphthyl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(1-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides;
With 2-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethylamino }-the 4-fluorobenzene, R
f0.39 (CH
2Cl
2/ methyl alcohol 45: 1), reaction obtains
N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides, 192-194 ℃;
With 2-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides;
With 2-{2-(4-(5-cyanoindole-3-yl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(5-cyanoindole-3-yl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides; Fumarate, m.p.214-216 ℃;
With 2-{2-(4-(6-cyanoindole-3-yl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(6-cyanoindole-3-yl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) cyclohexane carboxylic acid amides;
With 2-{2-(4-(1-naphthyl) piperidines-1-yl) ethylamino }-the 4-fluorobenzene, R
f0.44 (CH
2C1
2/ MeOH=30: 1), reaction obtains
N-{2-(4-(1-naphthyl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides, oxalate, m.p.223-225 ℃;
With 2-{2-(4-(2-naphthyl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(2-naphthyl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) cyclohexane carboxylic acid amides;
With 2-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides, fumarate, m.p.172-176 ℃;
With 2-{2-(4,4-diphenyl-piperidine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4,4-diphenyl-piperidine-1-yl) ethyl }-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides, R
f(0.55 methyl alcohol);
With 2-{2-(3-(3-fluoroform sulphonyl oxygen phenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(3-fluoroform sulphonyl oxygen phenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.134-136 ℃;
With 2-{2-(3-(4-fluoroform sulphonyl oxygen phenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(4-fluoroform sulphonyl oxygen phenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.180-184 ℃;
With 2-{2-(3-(biphenyl-3-yl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(biphenyl-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides, oxalate, m.p.103-106 ℃.
Similarly, by the adamantyl carbonyl chloride
With 2-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) adamantyl carboxylic acid amides, oxalate, m.p.107-110 ℃;
With 2-{2-(4-(1-naphthyl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(1-naphthyl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) adamantyl carboxylic acid amides, oxalate, m.p.123-126 ℃;
With 2-{2-(3-(2-methoxyphenyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) adamantyl carboxylic acid amides, oxalate, m.p.175-177 ℃.
Similarly, by Benzoyl chloride
With 2-{2-(3-(2-naphthyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(2-naphthyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) phenyl carboxamide, m.p.174-176 ℃.
Similarly, by 3-cyclopentyl propionyl chloride
With 2-{2-(3-(4-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(4-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl)-3-cyclopentyl propionic acid amide, oxalate, m.p.123-126 ℃.
Similarly, (can be by 3-(1-(2-phenyl amino ethyl) piperidin-4-yl) indoles-5-nitrile by 2-chloro-phenyl acetanilide,Phenacetylaniline and the reaction of 4-(5-cyanoindole-3-yl) piperidines, obtain 2-(4-(5-cyanoindole-3-yl) piperidines-1-yl)-phenyl acetanilide,Phenacetylaniline, reduce then and obtain) and " A " reaction obtain
N-{2-(4-(5-cyanoindole-3-yl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides, fumarate, m.p.198-200 ℃.
Similarly, by " A "
With N-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethyl } aniline reaction obtains
N-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides;
With N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl } aniline reaction obtains
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides;
Obtain with N-(2-(4-benzo (1,3) dioxole-5-phenylpiperidines-1-yl) ethyl) aniline reaction
N-{2-(4-benzo (1,3) dioxole-5-phenylpiperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides, R
f(0.75 methyl alcohol);
Obtain with N-(2-(4-(3-bromo-6-methoxyphenyl) piperidines-1-yl) ethyl) aniline reaction
N-{2-(4-(3-bromo-6-methoxyphenyl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides, fumarate, m.p.177-179 ℃;
Obtain with N-(2-(4-(3-fluoro-6-methoxyphenyl) piperidines-1-yl) ethyl) aniline reaction
N-{2-(4-(3-fluoro-6-methoxyphenyl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides, R
f(0.76 methyl alcohol), R
f(0.61 ethyl acetate);
Obtain with N-(2-(4-(3-fluoro-2 methoxyphenyls) piperidines-1-yl) ethyl) aniline reaction
N-{2-(4-(3-fluoro-2-methoxyphenyl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides, R
f(0.76 methyl alcohol), R
f(0.47 ethyl acetate);
Obtain with 3-(1-(2-phenyl amino ethyl) tetramethyleneimine 3-yl) indoles-5-nitrile reaction
N-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides;
Obtain with N-(2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl) aniline reaction
N-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides;
Obtain with N-(2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl) aniline reaction
N-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides;
Obtain with N-(2-(3-benzo (1,3) dioxole-5-base tetramethyleneimine-1-yl) ethyl) aniline reaction
N-{2-(4-(benzo (1,3) dioxole-5-yl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides, R
f(0.75 methyl alcohol);
Obtain with N-(2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl)-3-ethylaniline reaction
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(3-ethylphenyl) hexanaphthene carboxylic acid amides, R
f(0.78 methyl alcohol);
Obtain with N-(2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl)-4-ethylaniline reaction
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(4-ethylphenyl) hexanaphthene carboxylic acid amides, R
f(0.78 methyl alcohol);
Obtain with N-(2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl)-2-ethylaniline reaction
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-ethylphenyl) hexanaphthene carboxylic acid amides, R
f(0.74 methyl alcohol); Embodiment 2
1.02g (0.003mol) { 2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino }-2-pyridine and 0.3g (0.003mol) triethylamine are dissolved in the 20ml methylene dichloride.Under agitation drip 0.63g (0.003mol) chloroformic acid 2,2 that is dissolved in the 5ml methylene dichloride, 2-three chloro-ethyl esters.Then in stirring at room mixture 2 hours.Handle and purifying (eluent: ether/methyl alcohol 9: 1) on silicagel column with usual manner.
Output: 0.7gN-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) carboxylamine 2,2,2-three chloro-ethyl esters, m.p.140.8 ℃ (dihydrochloride).
Make following compound similarly:
N-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) carboxylamine 2,2,2-three chloro-ethyl esters;
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) carboxylamine 2,2,2-three chloro-ethyl esters;
N-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) carboxylamine 2,2,2-three chloro-ethyl esters;
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) carboxylamine 2-methyl propyl ester; Decompose＞80 ℃ (dihydrochloride);
N-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) carboxylamine 2-methyl propyl ester;
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) carboxylamine 2-methyl propyl ester;
N-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) carboxylamine 2-methyl propyl ester.Embodiment 3
With 1.02g{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino }-2-pyridine and 0.44g isocyanic acid 3-fluorophenyl ester stirred 2 hours under room temperature in 20ml THF.Remove desolvate and with the resistates that obtains with the silica gel column chromatography (elutriant: ethyl acetate/CH of purifying
3OH
9: 1).
Output: 0.9gN-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N '-(3-fluorophenyl)-N-(2-pyridyl) urea, m.p.199 ℃ (dihydrochloride).
Make following compounds similarly:
N-cyclohexyl-N '-{ 2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N '-(2-pyridyl) urea;
N-cyclohexyl-N '-{ 2-(3-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N '-(2-pyridyl) urea; M.p.159 ℃ (dihydrochloride);
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl)-N '-(4-trifluoromethyl) urea, m.p.187 ℃;
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2,4 difluorobenzene base)-N '-cyclohexyl urea, m.p.188 ℃.Embodiment 4
The solution of equivalent 4-(2-methoxyphenyl) piperidines, trifluoroacetic anhydride and triethylamine was stirred 1 hour under room temperature in methylene dichloride.After the conventional processing, obtain 4-(2-methoxyphenyl)-1-(trifluoroacetyl group) piperidines.React in methylene dichloride with trifluoroacetic anhydride and ammonium nitrate subsequently, after conventional processing, obtain 1: 1 mixture of compound 4-(2-methoxyl group-3-nitrophenyl)-1-(trifluoroacetyl group) piperidines and 4-(2-methoxyl group-5-nitrophenyl)-1-(trifluoroacetyl group) piperidines.Separate this mixture with silica gel chromatography, use hexane/EtOAc (4: 1-1: 1) make eluent.
By in ethanol with ammonium formiate and Pd/C reaction the carrying out reduction of nitro.After separating catalyst and the conventional processing, obtain the mixture of 4-(2-methoxyl group-3-aminophenyl)-1-(trifluoroacetyl group) piperidine carboxylic acid salt and 4-(2-methoxyl group-5-aminophenyl)-1-(trifluoroacetyl group) piperidine carboxylic acid salt.
By in aqueous hydrochloric acid with NaNO
2Reaction and under 0 to-10 ℃ of temperature, add 65% phosphofluoric acid (HPF subsequently
6) and amino is substituted with fluorine.After the conventional processing, heat solid stirred 1 hour, added the methanol solution of potassium hydroxide, and restir mixture 1 hour is also handled with usual manner, obtains 4-(3-fluoro-2-methoxyphenyl) piperidines and 4-(3-fluoro-6-methoxyphenyl) piperidines.With these two kinds of compounds and N-(2-oxoethyl)-N-Santosol 360 carboxylic acid amides, NaCNBH
3Be dissolved in together in the methyl alcohol with acetate, additionally stirred this mixture 3 hours.Obtain following compounds after the conventional processing:
N-{2-(4-(3-fluoro-2-methoxyphenyl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides, R
f(0.76 methyl alcohol), R
f(0.47 ethyl acetate) and
N-{2-(4-(3 fluoro-6-methoxyphenyl) piperidines-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides, R
f(0.76 methyl alcohol), R
f(0.61 ethyl acetate).
Similarly, by N-(2-oxoethyl)-N-Santosol 360 carboxylic acid amides
Obtain with the reaction of 3-(5-cyanoindole-3-yl) tetramethyleneimine
N-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides;
Obtain with the reaction of 3-(5-fluoro indole-3-yl) tetramethyleneimine
N-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-Santosol 360 carboxylic acid amides.Embodiment 5
2-(2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino) solution of pyridine in methylene dichloride is handled, this mixture was stirred 1 hour with the triethylamine of equivalent and piperidines-1-carboxylic acid trichloromethyl ester (" B) (can be obtained by trichlorine methoxy carbonyl chloride and piperidines reaction).After the conventional processing, obtain N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) piperidines-1-carboxylic acid amides.
Similarly, by " B "
With (R)-(+)-2-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
(R)-(+)-N-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) piperidines-1-carboxylic acid amides, fumarate, m.p.70-78 ℃; α
D 20(+) 2.8 ° (c1.0, methyl alcohol);
With (S)-(-)-2-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
(S)-(-)-N-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) piperidines-1-carboxylic acid amides, fumarate, m.p.70-78 ℃; α
D 20(-) 2.3 ° (c1.0, methyl alcohol);
Obtain with the reaction of 2-(2-(4-(5-fluoro indole-3-yl) piperidines-1 base) ethylamino) pyridine
N-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) piperidines-1-carboxylic acid amides, R
f0.19 (CH
2Cl
2/ methyl alcohol 9: 1);
With 2-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) piperidines-1-carboxylic acid amides, fumarate, m.p.136-139 ℃;
With 2-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(5-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(5-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(6-cyanoindole-3-yl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(3-(1-naphthyl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(1-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides, fumarate, m.p.85-90 ℃;
With 2-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(4-(5-cyanoindole-3-yl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(5-cyanoindole-3-yl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(4-(6-cyanoindole-3-yl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(6-cyanoindole-3-yl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(4-(1-naphthyl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(1-naphthyl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides, fumarate, m.p.172-175 ℃;
With 2-{2-(4-(2-naphthyl) piperidines-1-yl) ethylamino }-4-fluorobenzene reaction obtains
N-{2-(4-(2-naphthyl) piperidines-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides;
With 2-{2-(3-(3-trifluoro-methanesulfonyl oxy phenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(3-trifluoro-methanesulfonyl oxy phenyl) tetramethyleneimine-1-yl) ethyl }-N-(4-fluorophenyl) piperidines-1-carboxylic acid amides.
Similarly, by tetramethyleneimine-1-carboxylic acid three chloromethyl esters
With 2-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine reaction obtains
N-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) tetramethyleneimine-1-carboxylic acid amides, EI394
With 2-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethylamino } pyridine reaction obtains
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) tetramethyleneimine-1-carboxylic acid amides, R
f(0.55 methyl alcohol).
Similarly, by 2-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethylamino } pyridine
Obtain with a word used for translation heptane (azepane)-1-carboxylic acid three chloromethyl esters reaction
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) a word used for translation heptane-1-carboxylic acid amides, R
f(0.46 methyl alcohol);
Obtain with 2-ethyl piperidine-1-carboxylic acid three chloromethyl esters reaction
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl)-2-ethyl piperidine-1-carboxylic acid amides, R
f(0.52 methyl alcohol);
Obtain with 3-ethyl piperidine-1-carboxylic acid three chloromethyl esters reaction
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl)-3-ethyl piperidine-1-carboxylic acid amides, R
f(0.55 methyl alcohol);
Obtain with 4-ethyl piperidine-1-carboxylic acid three chloromethyl esters reaction
N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl)-4-ethyl piperidine-1-carboxylic acid amides, R
f(0.6 methyl alcohol); Embodiment 6
By the ether hydrolysis, by 2-{2-(3-(3-methoxyphenyl) tetramethyleneimine-1-yl) ethylamino } pyridine, R
f0.28 (CH
2Cl
2/ CH
3OH19: 1), obtain
2-{2-(3-(3-hydroxy phenyl) tetramethyleneimine-1-yl) ethylamino } pyridine, R
f0.26 (CH
2Cl
2/ CH
3OH9: 1).Embodiment 7
Separate diastereomer and enantiomorph with preparation HPLC by analysis
Carry out following separation with following method: a) 4-(2-methoxyphenyl) pyrrolidone
Separate:
Post: chiral column
Elutriant: tetrahydrofuran (THF)
Each amount of loading: 55mg
Fractional dose: 55mg
Output: each enantiomorph is 20mg (first enantiomorph: (α) in each case
20 D=+44 °, in methyl alcohol) b) 3-(3-methoxyphenyl) succinimide
Separate:
Post: chiral column
Elutriant: heptane/ethanol (60: 40)
Each amount of loading: 300mg
Fractional dose: 5.3g
Output: the first enantiomorph 1.8g ((α)
20 D=-92.1 °, in methyl alcohol, m.p.85.8 ℃), second enantiomorph 0.89 ((α)
20 D=+93 °, in methyl alcohol, m.p.85.9 ℃) c) 4-(2-naphthyl) pyrrolidone
Separate:
Post: chiral column
Elutriant: tetrahydrofuran (THF)
Each amount of loading: 200mg
Fractional dose: 4g
Output: 1.52g first enantiomorph ((α)
20 D=-47.2 °, in methyl alcohol)
1.46g second enantiomorph ((α)
20 D=+40 °, in methyl alcohol; M.p.130.2 ℃) d) (1,4-benzodioxan-6-yl)-4-pyrrolidone
Separate:
Post: cellulosic triacetate or Chiracel OJ
With Chiracel OD
Elutriant: methyl alcohol or hexane/2-propyl alcohol (90: 10)
The following example relates to the preparation of raw material: embodiment 8a)
Be dissolved in 6.01g5-fluoro indole and 8.67g maleimide in the glacial acetic acid and under refluxad heated 120 hours.This section reaction times is difficult to detect this two kinds of raw materials by tlc later.Concentrated reaction mixture obtains a resistates.The solvent mixture stirring that this resistates is made up of 9: 1 ether and methylene dichloride with 200ml 2.5 hours.Be settled out yellow crystal, suction strainer is also dry.Concentrated mother liquor obtains a resistates, and it is stirred with the above-mentioned solvent mixture of 50ml.Be settled out fresh yellow crystal like this, suction strainer is also dry.
Output: 7.84g3-(succinimide-3-yl)-5-fluoro indole (yellow crystal); R
f0.25 (elutriant: ethyl acetate/petroleum ether 1: 1).b)
7.84g3-(succinimide-3-yl)-5-fluoro indole is dissolved among the 250ml THF.Slowly drip two (methoxy ethoxy) aluminium sodium (Vitride of 48.8g hydrogenation then
).Make gaseous volatilization, the brown solution blackening, and almost be warmed to boiling point.Under refluxad heated this solution 12-16 hour.After the cooling, use treatment reaction solution.Suction strainer gained precipitation and concentrated mother liquor.Resistates is dissolved in ethyl acetate and the hydrochloric acid (2N).Isolated ethyl acetate is with hydrochloric acid washed twice again.With 32%NaOH water is transferred to the alkaline pH value.Use the dichloromethane extraction water then several times.Use MgSO
4Dry organic phase is filtered and is concentrated, and obtains a resistates.Resistates A:1.2g (dark-brown, thick substances).With n-butanol extraction alkalescence water once.The same butanols phase that concentrates obtains resistates.Resistates B:2.6g (need not to handle and further processing).Output: 3.8g3-(tetramethyleneimine-3-yl)-5-fluoro indole (black, thickness oily matter, contaminated).c)
With 3.8g3-(tetramethyleneimine-3-yl)-5-fluoro indole (A+B) the 250ml trimethyl carbinol and 250ml 1M NaHCO
3The aqueous solution is handled.Slowly drip 8.73g heavy carbonic di tert butyl carbonate (di-tert-butyl dicarbonate) then with-a little trimethyl carbinols dilutions.Obtain brown suspension, with its at room temperature stir about 12-16 hour.Extract this suspension by water and ether jolting.Use MgSO
4Dry organic phase is filtered and is concentrated on Rotavapor.Obtain the brown oily resistates of 2.6g.With column chromatography (silica gel 60) this crude product (elutriant: ethyl acetate/petroleum ether 4: 1) of purifying.
Output: 1.5g3-(N-tertbutyloxycarbonyl tetramethyleneimine-3-yl)-5-fluoro indole (brown resistates), R
f0.55 (elutriant: petrol ether/ethyl acetate 2: 1).d)
400mg3-(N-tertbutyloxycarbonyl tetramethyleneimine-3-yl)-5-fluoro indole is dissolved in the 50ml ethanol also with the acid treatment of 5ml salt.This solution was at room temperature placed 1 hour.Concentrate this solution and obtain a resistates, it is used 1N NaHCO
3Solution and EA handle, by the shaking out mixture and separate each phase.Organic phase MgSO
4Drying is filtered and the use vacuum rotary evaporator concentrates.Resistates is dissolved in EA and uses the 117.95mg oxalic acid treatment, be dissolved in some acetone.Be settled out crystallization, with its suction strainer and dry.
Output: 300mg3-(tetramethyleneimine-3-yl)-5-fluoro indole oxalate (dusty blue crystallization), m.p.175 ℃ (decomposition).e)
With aniline, 2-bromo-1,1-diethoxyethane and NaHCO
3Solution in DMF heated 20 hours down at 100 ℃.After the conventional processing, obtain N-(2,2-diethoxy ethyl) aniline.React in methylene dichloride with hexanaphthene carbonyl chloride and triethylamine subsequently, obtain N-(2,2-diethoxy ethyl)-N-Santosol 360 carboxylic acid amides.
Use 10% oxalic acid aqueous solution and 15% sulfuric acid fracture acetal.Obtain N-(2-oxoethyl)-N-Santosol 360 carboxylic acid amides after the conventional processing.
Obtain following compounds similarly:
N-(2-oxoethyl)-N-(2-ethylphenyl) hexanaphthene carboxylic acid amides,
N-(2-oxoethyl)-N-(3-ethylphenyl) hexanaphthene carboxylic acid amides,
N-(2-oxoethyl)-N-(4-ethylphenyl) hexanaphthene carboxylic acid amides and
N-(2-oxoethyl)-N-(4-fluorophenyl) hexanaphthene carboxylic acid amides.
The following example relates to pharmaceutical preparation:
Embodiment A: injection small jar:
Solution in 3 liters of redistilled waters is adjusted to pH6.5 with 2N hydrochloric acid with 100g formula I active compound and 5g Sodium phosphate dibasic, and sterile filtration is filled in the injection small jar and freeze-drying under aseptic condition, this small jar of sterile seal.Each is injected small jar and contains the 5mg active compound.
Embodiment B: suppository
The mixture of 20g formula I active compound and 100g soybean lecithin and 1400g theobroma oil is merged also cooling in the impouring mould.Each suppository contains the 20mg active compound.
Embodiment C: solution
By 1g formula I active compound, 9.38gNaH
2PO
42H
2O, 28.48gNa
2HPO
412H
2O and the solution of 0.1g Zephiran chloride preparation in the 940ml redistilled water.PH is transferred to 6.8, this solution is made into 1 liter and irradiation sterilization.
Embodiment D: ointment
500mg formula I active compound is mixed under aseptic condition with 99.5g Vaseline.
Embodiment E: tablet
The mixture of 1kg formula I active compound, 4kg lactose, 1.2kg potato starch, 0.2kg talcum and 0.1kg Magnesium Stearate is compressed in a usual manner, obtain the tablet that each sheet contains the 10mg active compound.
Embodiment F: coated tablet
Be similar to embodiment E, compressed tablets, the coating with sucrose, potato starch, talcum, tragacanth gum and tinting material coats in a usual manner then.
Embodiment G: capsule
2kg formula I active compound is filled in the hard gelatin capsule in a usual manner, and each capsule contains the 20mg active compound.
Embodiment H: ampoule
With the solution sterile filtration of 1kg formula I active compound in 60 liters of redistilled waters, be filled in the ampoule freeze-drying under aseptic condition, and sterile seal ampoule.Each ampoule contains the 10mg active compound.
Claims (10)
1. formula I compound and salt thereof:
R wherein
1For not replacing or by A, A-O-, OH, Hal, CN, NO
2, NH
2, A and/or-O-SO
2CF
3Single replacement, two replaces or trisubstd phenyls,
Do not replace or replace or dibasic 2-or 3-indyl by A, A-O-, OH, Hal and/or CN are single,
1,4-benzodioxan-5-or-6-base or
1-or 2-naphthyl, R
2Be phenyl or pyridyl, it is not substituted or replaces or two replacements R by A, A-O-, OH, Hal and/or CN are single
3Be H, A, A-O-, Ph, NHR
4Or NR
5R
6, R
4Be phenyl or pyridyl, it is not substituted or replaces or two replacements by A, A-O-, OH, Hal and/or CN are single, or for having the cycloalkyl of 3-10 carbon atom, R
5And R
6Together for having the alkylidene chain of 4,5 or 6 carbon atoms, A is the straight or branched alkyl with 1-10 carbon atom, it can be replaced by 1-5 F and/or Cl atom, or for having the cycloalkyl of 3-10 carbon atom, Hal is F, Cl, Br or I, and k and l are 0 or 1 independently of one another, and m is 0,1 or 2, and n is 1 or 2, and condition is k k=0 when being not equal to l and m=2.
2. according to the steric isomer of the formula I compound of claim 1.
3. according to the compound and the salt thereof of claim 1 or 2,
A) N-{2-(4-(2-methoxyphenyl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
B) N-{2-(4-(5-fluoro indole-3-yl) piperidines-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
C) N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
D) N-{2-(3-(2-methoxyphenyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
E) N-(2-(3-(1,4-benzodioxan-6-yl) tetramethyleneimine-1-yl) ethyl)-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
F) N-(2-(3-(6-fluoro indole-3-yl) tetramethyleneimine-1-yl) ethyl)-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
G) N-(2-(3-(7-methoxyl group-2-naphthyl) tetramethyleneimine-1-yl) ethyl)-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
H) R-(+)-N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
I) S-(-)-N-{2-(3-(2-naphthyl) tetramethyleneimine-1-yl) ethyl }-N-(2-pyridyl) hexanaphthene carboxylic acid amides;
J) N-(2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl)-N '-(3-fluorophenyl)-N-(2-pyridyl) urea;
K) N-cyclohexyl-N '-(2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl)-N '-(2-pyridyl) urea;
L) N-cyclohexyl-N '-(2-(3-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl)-N '-(2-pyridyl) urea;
M) N-(2-(4-(6-fluoro indole-3-yl) piperidines-1-yl) ethyl)-N-(2-pyridyl)-N '-(4-trifluoromethyl) urea.
4. preparation is characterized in that according to the method for the formula I compound of claim 1
A) make formula II compound
R wherein
1, R
2, the implication that m and n have in the claim 1 to be given is reacted with formula III compound
R
3-CO-L (III) wherein L is the OH group of Cl, Br, I or free or reactive functional modification, and
R
3The implication that has in the claim 1 to be given, perhaps
B) make formula IV compound
R wherein
1With the implication that n has in the claim 1 to be given, react with formula V compound
Wherein L is the OH group of Cl, Br, I or free or reactive functional modification, and
R
2, R
3, m, k and the l implication that has in the claim 1 to be given, perhaps
C) in the reductive amination reaction, make formula VI compound
R wherein
2, R
3, m, k and the l implication that has in the claim 1 to be given, with the reaction of formula IV compound, perhaps
D) make formula VII compound
R wherein
2And R
3The implication that has in the claim 1 to be given is reacted with formula VIII compound
Wherein L is the OH group of Cl, Br, I or free or reactive functional modification, and
R
1, m and the n implication that has in the claim 1 to be given, perhaps
E) make the acid amides of formula VII, wherein R
2And R
3Have above-mentioned implication, with the reaction of formula IX compound,
R wherein
1, n and the m implication and the Q that have in the claim 1 and given be the OH group of Cl, Br, I or free or reactive functional modification, perhaps
F) make formula X compound
R wherein
1, R
3, m and the n implication that has in the claim 1 to be given, phenyl or pyridinyl derivatives reaction with suitable obtain formula I compound, the latter can at random be converted into another formula I compound, perhaps
G) in order to prepare wherein R
3Be NHR
4And R
4The formula I compound of the implication that has in the claim 1 to be given,
Make wherein R
1, R
2, m and the n implication that has in the claim 1 to be given formula II compound and the reaction of formula XI compound
R
3-N=C=O (XI) is R wherein
3The implication that has in the claim 1 to be given, and/or be by with acid treatment the basic cpd of formula I being converted into its a kind of salt.
5. produce the method for pharmaceutical preparation, it is characterized in that will be according to the salt that tolerates on the formula compound of claim 1 and/or its a kind of physiology, and suitable agent shape is made in its a kind of enantiomorph or diastereomer and at least a solid, liquid or semiliquid vehicle or auxiliary agent and suitable words and one or more other active compounds combinations.
6. pharmaceutical preparation is characterized in that it contains at least a compound and/or its a kind of physiologically acceptable salt according to one of claim 1 and 2.
7. according to the formula I compound of claim 1 and its physiologically acceptable salt, the disease that is used to keep on a diet, dysacousis, age dependent form dysmnesia, tardive dyskinesia and be used for favourable influence obsessional idea and behavior.
8. according to the formula I medicine and the physiologically acceptable salt thereof of claim 1, be used as 5-HT with 5-HT reuptake inhibition, antidepressant effect or angst resistance effect
1AAntagonist.
9. the purposes in producing medicine according to the formula I compound of claim 1 and/or its physiologically acceptable salt.
10. according to the formula I compound and/or the purposes of its physiologically acceptable salt in the disease of keeping on a diet, dysacousis, age dependent form dysmnesia, tardive dyskinesia and favourable influence obsessional idea and behavior of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97193878 CN1223650A (en) | 1996-04-18 | 1997-04-14 | Piperidines and pyrrolidines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19615232.1 | 1996-04-18 | ||
| CN 97193878 CN1223650A (en) | 1996-04-18 | 1997-04-14 | Piperidines and pyrrolidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1223650A true CN1223650A (en) | 1999-07-21 |
Family
ID=5179112
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97193878 Pending CN1223650A (en) | 1996-04-18 | 1997-04-14 | Piperidines and pyrrolidines |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1223650A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117003693A (en) * | 2022-05-05 | 2023-11-07 | 四川大学华西医院 | Piperidine derivatives, preparation method and application thereof |
-
1997
- 1997-04-14 CN CN 97193878 patent/CN1223650A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117003693A (en) * | 2022-05-05 | 2023-11-07 | 四川大学华西医院 | Piperidine derivatives, preparation method and application thereof |
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