CN1721408A - 1-benzyl tetrahydro isoquinoline compound, its preparing process and use thereof - Google Patents
1-benzyl tetrahydro isoquinoline compound, its preparing process and use thereof Download PDFInfo
- Publication number
- CN1721408A CN1721408A CN 200510026469 CN200510026469A CN1721408A CN 1721408 A CN1721408 A CN 1721408A CN 200510026469 CN200510026469 CN 200510026469 CN 200510026469 A CN200510026469 A CN 200510026469A CN 1721408 A CN1721408 A CN 1721408A
- Authority
- CN
- China
- Prior art keywords
- compound
- tetrahydro isoquinoline
- benzyl tetrahydro
- gat
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention belongs to the field of medicine synthesis, and is new type of N-alkyl side chain/N-acyl side chain substituted 1-benzyl tetrahydro isoquinoline compound and its preparation process and GAT-1 inhibiting activity application. The present invention improves the structure of natural 1-benzyl tetrahydro isoquinoline compound to synthesize N-alkyl side chain/N-acyl side chain substituted 1-benzyl tetrahydro isoquinoline compound derivative. The extracorporeal GABA transport protein (GAT-1) competitive inhibiting combination test shows that the derivative has GAT-1 inhibiting activity, obviously higher than that of contrast (R)-3-piperidyl formic acid. The compound of the present invention may be used in further preparing GAT-1 inhibitor and medicine for treating neurogenic or psychogenic diseases, such as epilepsy, anxiety, chronic pain and insomnia.
Description
Technical field:
The invention belongs to the synthetic field of medicine, be specifically related to the 1-benzyl tetrahydro isoquinoline compound that novel cpd N-alkyl side chain/N-acyl side-chain replaces, and its production and application.
Background technology:
γ-An Jidingsuan (GABA) is the main inhibitory nerve mediator in the mammal central nervous system (CNS), with the common normal function of coordinating to keep brain of excitatoty neurotransmitter.Nearly 20%～40% cynapse is neurotransmitter with GABA in the brain according to statistics, and GABA is subjected to the accuracy controlling of the GABA translocator of multiple hypotype.The GAT-1 hypotype is high expression level on the cortical neuron presynaptic membrane, is the major protein that participates in the GABA reuptake.The GAT that is positioned near the spongiocyte of GABA serotonergic neuron has the transmission of the inhibitory synapse of termination signal, the function of regulating the cynapse of GABA energy.Has the function of removing the GABA that diffuses out away from the GAT on the GABA serotonergic neuron spongiocyte.In addition, spongiocyte reuptake GABA is to the presynaptic GABA of excitability tip
BAcceptor may play regulating effect.GABA can be repeated to utilize at presynaptic neuron by the GAT reuptake on the synapse cephacoria, has reduced the synthetic again of GABA.GABA by the GAT reuptake on the spongiocyte after, by the rapid metabolism of GABA transaminase.In central nervous system disease, reduction, the especially epilepsy that GABA energy nerve signal transmits appears in regular meeting.It is reported that the sickness rate of epilepsy is about 0.5%～0.7% in central nervous system disease.The U.S. has 2,500,000 people to suffer from epilepsy approximately, wherein has 800,000 people to be partial seizures approximately, and the New Development patient of annual epilepsy has 12.5 ten thousand people, and continues to faint from fear after at least 65 ten thousand people's medications.The World Health Report of WHO1995 estimates at 0.3 hundred million people and suffers from epilepsy.China's epilepsy invasion rate is also higher, and is about about 9,000,000, especially the teenager.Discover that GAT-1 has become the main target spot of screening antiepileptic drug at present.GAT-1 nervosa or psychotic disorder also relate to as anxiety, diseases such as chronic pain or insomnia.
Recently there is research also to find in tissue especially cerebral tissue, to exist the compound of tetrahydroisoquinoline structure.Salsolinol as following structure not only can induce nerve cell death, and can cause dna damage and have the genotoxicity effect.Tetrahydropapaveroline (THP) is the compound of the 1-benzyl tetrahydro isoquinoline alkaloid structure found in Parkinson patient's cerebral tissue and urine.Bicuculline separates and next 2-benzo [C] furanone isoquinoline alkaloid from the Fumaraceae plant.Pharmacological research shows that Bicuculline is the selective antagonist of GABA acceptor, uses as an ideal tools medicine studying the GABA receptor acting at present.
In research process to the GABA transporter inhibitors, Krogsgaard-Larsen etc. are incorporated into similar gamma-aminobutyric acid with phenylbenzene butenyl side chain and are become on the fused heterocycle nitrogen-atoms behind the piperidines by molecule inner ring condensation, as be introduced into the compound (N-DPB-THPO) that obtains on the nitrogen-atoms of tetrahydrochysene isoxazole piperidines alcohol, have GABA transporter inhibitors activity equally.
Summary of the invention:
The purpose of this invention is to provide a kind of inhibiting novel N-alkyl side chain of good GAT-1/N-acyl side-chain replacement 1-benzyl tetrahydro isoquinoline compound that has.
The present invention is according to the bioisostere principle, the phenyl ring of tetrahydrochysene isoxazole ring in the N-DPB-THPO structure with its bioisostere such as fragrance substituted, introduce the 1-benzyl tetrahydro isoquinoline compound of the basic butenyl side chain of lipophilic hexichol (mixing) on the synthetic N atom, or introduce the 1-benzyl tetrahydro isoquinoline compound of the basic oxime ether of lipophilic hexichol (mixing) side chain on the N atom.
The present invention has transformed natural 1-benzyl tetrahydro isoquinoline compound structure, the 1-benzyl tetrahydro isoquinoline derivative that synthetic N replaces.Specifically comprise the 1-benzyl tetrahydro isoquinoline derivative that N-alkyl side chain or N-acyl side-chain replace.
The compounds of this invention in conjunction with experiment test, has shown that certain GAT-1 suppresses active by the external competitive inhibition of preliminary GABA translocator (GAT-1), and described compound can further prepare novel GAT-1 inhibitor medicaments.
The compounds of this invention N-alkyl side chain/N-acyl side-chain replaces the 1-benzyl tetrahydro isoquinoline compound and has following formula structure I:
Wherein, R
1=H or CH
3Or other alkyl;
R
2=H or CH
3Or other alkyl;
(wherein, Ar
1=phenyl or substituted-phenyl or fragrant heterocycle or replacement virtue heterocycle;
Ar
2=phenyl or substituted-phenyl or fragrant heterocycle or replacement virtue heterocycle;
R
3The alkyl side chain of=replacement)
Preferred compounds of the invention are compound with following 1,2,3 structures,
In conjunction with experiment test, the result shows that having certain GAT-1 suppresses active to above-claimed cpd by the external competitive inhibition of GABA translocator (GAT-1).
Another technical problem to be solved by this invention provides the preparation method that above-mentioned N-alkyl side chain or N-acyl side-chain replace the 1-benzyl tetrahydro isoquinoline compound.
N-alkyl side chain disclosed by the invention or N-acyl side-chain replace the 1-benzyl tetrahydro isoquinoline compound and can be obtained by following reaction scheme.
Route 1
Route 2
The embodiment of the invention 1 is described the preparation method of compound 1 in detail, preparation process as shown in the formula:
The preparation technology of compound 1 comprises: with 3,4-dimethoxy-phenylethylamine and 3, the 4-dimethoxyphenylacetic acid is that raw material adds thermal condensation and gets 2-(3 under 180～200 ℃ of conditions, the 4-Dimethoxyphenyl)-N-[2-(3, the 4-Dimethoxyphenyl) ethyl] ethanamide 4,4 carry out the Bischler-Napieralski ring-closure reaction under effects such as dewatering agent Phosphorus Oxychloride gets compound 5,5 and is reduced reductive compound such as agent sodium borohydride 6,6 and gets compound 1 with acid 7 condensation under the EDCI/HOBT effect.
The embodiment of the invention 2 is described the preparation method of compound 2 in detail, preparation process as shown in the formula:
The preparation technology of compound 2 comprises:
With 3,4-dimethoxy-phenylethylamine and 3, the 4-dimethoxyphenylacetic acid is that raw material adds thermal condensation and gets 2-(3 under 180～200 ℃ of conditions, the 4-Dimethoxyphenyl)-N-[2-(3, the 4-Dimethoxyphenyl) ethyl] ethanamide 4,4 carry out the Bischler-Napieralski ring-closure reaction under effects such as dewatering agent Phosphorus Oxychloride gets compound 5,5 and is reduced reductive compound such as agent sodium borohydride 6,6 and gets compound 2 with acid 8 condensation under the EDCI/HOBT effect.
The embodiment of the invention 3 is described the preparation method of compound 3 in detail, preparation process as shown in the formula:
The preparation technology of compound 3 comprises:
With 3,4-dimethoxy-phenylethylamine and 3, the 4-dimethoxyphenylacetic acid is that raw material adds thermal condensation and gets 2-(3 under 180～200 ℃ of conditions, the 4-Dimethoxyphenyl)-N-[2-(3, the 4-Dimethoxyphenyl) ethyl] ethanamide 4,4 carry out the Bischler-Napieralski ring-closure reaction under effects such as dewatering agent Phosphorus Oxychloride gets compound 5,5 and is reduced reductive compound such as agent sodium borohydride 6,6 and gets compound 3 with bromo-derivative 9 condensation under the EDCI/HOBT effect.
Another technical problem to be solved by this invention is to disclose above-mentioned novel N-alkyl side chain/N-acyl side-chain to replace the application of 1-benzyl tetrahydro isoquinoline compound as the GAT-1 inhibitor.The novel N-alkyl side chain of the present invention/N-acyl side-chain replaces the 1-benzyl tetrahydro isoquinoline compound by passing through the external competitive inhibition of preliminary GABA translocator (GAT-1) in conjunction with experiment test; the result shows activity all apparently higher than positive control (R)-nipecotic acid, shows that having GAT-1 suppresses active.The GAT-1 inhibitor be can further prepare and treatment nervosa or psychotic disorder such as epilepsy, anxiety, the medicine of chronic pain or insomnia comprised.
Embodiment:
Embodiment 1: synthetic compound 1 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-N-acyl derivative (1)
1) Synthetic 2-(3, the 4-Dimethoxyphenyl)-N-[2-(3, the 4-Dimethoxyphenyl) ethyl] ethanamide (3)
In the 250ml reaction flask, add 3,4-dimethoxy-phenylethylamine 21.5g (118mmol) and 3,4-dimethoxyphenylacetic acid 23.3g (118mmol), be heated to 190～200 ℃ of reactions 2 hours, cooling is with ethyl acetate 30ml solvent reaction thing, with (4 * 20ml) washings of 1N hydrochloric acid, saturated sodium bicarbonate liquid (4 * 20ml) washings, saturated common salt water washing, anhydrous magnesium sulfate drying.Boil off partial solvent, add chloroform 10ml again, this moment have solid to separate out, the cooling, suction filtration, white solid 3:32.9g (yield: 77.5%), m.p:122-124 ℃.
1HNMR(300MHz，CDCl
3)：δ2.68(t，2H，J＝6.9Hz)，3.43(t，2H，J＝6.9Hz)，3.48(s，2H，-CH
2CONH-)，3.85(s，4H，-OCH
3)，3.86(s，2H，-OCH
3)，3.89(s，2H，-OCH
3)，6.62～6.74(m，5H，PhH).EIMS(m/z，％)：359(M
+，9.28)，195(3.56)，164(99.90)，151(100.00)，135(8.75)，107(24.11).FT-IR(KBr)v3326，2915，1716，1642，1519，1229，1144，1027，806，704.
2) synthetic 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9 (4)
Compound 31.27g (3.93mmol) is dissolved in dry toluene 30ml; under the nitrogen protection; heating adds phosphorus oxychloride 1.8ml (being dissolved in the 20ml dry toluene), heating reflux reaction 3 hours after making the solid dissolving again; the complete solvent that removes under reduced pressure of reaction; residuum is dissolved among the methylene dichloride 30ml, is 8～9 with the strong aqua adjust pH, merges organic phase; water (1 * 10ml) washing, anhydrous magnesium sulfate drying.Filter, filtrate steaming removal solvent, faint yellow solid, use recrystallizing methanol, must compound 4:0.91g (yield: 75%), m.p.116～118 ℃.
1HNMR(300MHz，CDCl
3)：δ2.82(t，2H，J＝7.5Hz)，3.79(s，2H，-CH
2PhH)，3.89～3.92(m，2H)，3.94(s，12H，-OCH
3)，6.76～6.91(m，3H，PhH)，7.59～7.68(m，2H，PhH).EIMS(m/z，％)：341(M
+，1.61)，324(100.00)，312(94.91)，165(75.77)，137(14.47)，77(23.71).FT-IR(KBr)v 2970，1660，1515，1280，1135，1024，867，792，755.
3) synthetic 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5)
In the 50ml reaction flask, add compound 4 196mg (57.4mmol), methylene dichloride 15ml, methyl alcohol 10ml under the ice-water bath, adds sodium borohydride 65mg (1.72mmol), be raised to room temperature reaction gradually 3 hours, add entry 5ml, (2 * 20ml) extractions merge organic phase with methylene dichloride, with less water and saturated common salt water washing, Anhydrous potassium carbonate drying.Boil off solvent, white solid, use recrystallizing methanol, must compound 5:162mg (yield: 82%), m.p.135～137 ℃.
1HNMR(300MHz，CDCl
3)：δ2.56～2.57(m，2H)，2.85～2.88(m，2H)，3.43～3.44(m，1H)，3.74(s，3H，-OCH
3)，3.86(s，9H，-OCH
3)，5.01～5.02(m，1H)，6.55～6.84(m，5H，PhH).EIMS(m/z，％)：343(M
+，1.77)，192(100.00)，176(36.64)，167(12.23)，139(26.54)，118(13.02).FT-IR(KBr)v 3299，2939，1609，1642，1516，1322，1257，1024，775.
4) synthetic 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-N-acyl derivative (1)
In the 50ml reaction flask, add raw material acid 6 224mg (0.91mmol), methylene dichloride 10ml, add DMF 3ml again, add HOBT 138mg (1.00mmol), be chilled to-20 ℃, add EDCI 196mg (1.00mmol), keep-20 ℃ of reactions 1 hour, at room temperature reacted again 1 hour, and added compound 5 344mg (1.00mmol) then, room temperature reaction 15 hours, add entry 5ml, layering, (2 * 20ml) extractions merge organic phase with methylene dichloride, with 1N hydrochloric acid (1 * 5ml), (1 * 5ml) washing is again with less water and saturated common salt water washing, Anhydrous potassium carbonate drying for saturated sodium bicarbonate solution.Boil off solvent, silica gel column chromatography (elutriant: sherwood oil: ethyl acetate=3: 1), compound 1:393mg (yield: 75.6%), white solid, m.p.180～182 ℃.
1HNMR(300MHz，CDCl
3)：δ2.56～2.57(m，2H)，2.85～2.88(m，2H)，3.43～3.44(m，1H)，3.74(s，3H，-OCH
3)，3.86(s，9H，-OCH
3)，5.01～5.02(m，1H)，6.55～6.84(m，5H，PhH).ESI-MS：571(M+H)
+，594(M+Na)
+，610(M+K)
+.HRMS(ESI)：Calcd forC
35H
41NO
6+Na：594.2824840，Found 594.2826091.FT-IR(KBr)v 2933，1736，1639，1516，1465，1261，1115，1026，804.
Embodiment 2: synthetic compound 2 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-N-acyl derivative (2)
1) Synthetic 2-(3, the 4-Dimethoxyphenyl)-N-[2-(3, the 4-Dimethoxyphenyl) ethyl] ethanamide (3)
The method of synthetic compound 3 is with 3 synthetic method unanimity in the compound 1.
2) synthetic 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9 (4)
The method of synthetic compound 4 is with 4 synthetic method unanimity in the compound 1.
3) synthetic 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5)
The method of synthetic compound 5 is with 5 synthetic method unanimity in the compound 1.
4) synthetic 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-N-acyl derivative (2)
In the 50ml reaction flask, add raw material acid 7 163mg (0.86mmol), methylene dichloride 10ml, add DMF 3ml again, add HOBT 130mg (0.94mmol), be chilled to-20 ℃, add EDCI 185mg (0.94mmol), keep-20 ℃ of reactions 1 hour, at room temperature reacted again 1 hour, and added compound 5 323mg (0.94mmol) then, room temperature reaction 15 hours, add entry 5ml, layering, (2 * 20ml) extractions merge organic phase with methylene dichloride, with 1N hydrochloric acid (1 * 5ml), (1 * 5ml) washing is again with less water and saturated common salt water washing, Anhydrous potassium carbonate drying for saturated sodium bicarbonate solution.Boil off solvent, silica gel column chromatography (elutriant: sherwood oil: ethyl acetate=1: 1), compound 2:316mg (yield: 71.8%), white solid, m.p.105～107 ℃.
1HNMR(300MHz，CDCl
3)：δ1.14～1.29(m，3H)，1.41(s，6H，-COOC(CH
3)
3)，1.43(s，3H，-COOC(CH
3)
3)，2.57～3.01(m，3H)，3.04～3.12(m，2H)，3.32～3.59(m，1H)，3.71(s，3H，-OCH
3)，3.76(s，3H，-OCH
3)，3.78(s，3H，-OCH
3)，3.84(s，3H，-OCH
3)，4.59～4.74(m，1H)，5.53～5.76(m，1H)，6.37～6.42(m，1H)，6.52～6.77(m，4H).ESI-MS：515(M+H)
+，537(M+Na)
+，553(M+K)
+.HRMS(ESI)：Calcd for C
28H
38N
2O
7+Na：537.2575640，Found 537.2571227.FT-IR(KBr)v 3425，3319，2935，1708，1642，1517，1452，1260，1160，1028，861.
Embodiment 3: synthetic compound 3 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-N-alkyl derivative (3)
1) Synthetic 2-(3, the 4-Dimethoxyphenyl)-N-[2-(3, the 4-Dimethoxyphenyl) ethyl] ethanamide (3)
The method of synthetic compound 3 is with 3 synthetic method unanimity in the compound 1.
2) synthetic 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9 (4)
The method of synthetic compound 4 is with 4 synthetic method unanimity in the compound 1.
3) synthetic 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5)
The method of synthetic compound 5 is with 5 synthetic method unanimity in the compound 1.
4) 1-(3, the 4-dimethoxy) benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-N-alkyl derivative (3)
In the 50ml reaction flask, add compound 5120mg, DMF 6ml, add compound 9114mg, add acetone 20ml again, potassiumiodide 6mg, and salt of wormwood 48mg, stirring at room reaction 50 hours, the pressure reducing and steaming solvent adds methylene dichloride 20ml in the resistates, with less water and saturated common salt water washing, Anhydrous potassium carbonate drying.Boil off solvent, silica gel column chromatography (elutriant: sherwood oil: ethyl acetate=1: 1), white solid, 3:200mg, m.p.194～196 ℃, yield: 90%.
1HNMR(300MHz，CDCl
3)：δ2.24～2.46(m，1H)，2.73～3.07(m，4H)，3.19～3.24(m，1H)，3.62(s，3H，-OCH
3)，3.77(s，3H，-OCH
3)，3.80(s，3H，-OCH
3)，3.82(s，3H，-OCH
3)，3.83～3.92(m，2H)，4.26～4.34(m，2H)，4.61～4.64(m，1H)，6.05～6.07(m，1H，PhH)，6.54～6.94(m，4H，PhH)，7.28～7.44(m，10H，PhH).ESI-MS：567(M+H)
+.
The external competitive inhibition of embodiment 4.GABA translocator (GAT-1) is in conjunction with experiment
1) instrument of Shi Yonging and reagent:
Used instrument: liquid dodges numeration instrument (Beckman LS 5000TA), thermostat water bath, electronic balance, liquid-transfering gun, stopwatch etc.
Reagent: PPO:2, and the 5-diphenyl-oxazole (2,5-diphenyloxazole); POPOP:1,4-pair-[5-phenyl-2-oxazolyl] benzene (1,4-Bis-[5-phenyl-2-oxazoyl]-benzene); RMPI 1640 substratum that contain 10% calf serum; [
3H] GABA:(AmershamPharmacia Biotech).
Reagent preparation: the PBS:(phosphate buffered saline(PBS)): dissolving 8g NaCl in 800ml distilled water, 0.2g KCl, 1.44g Na
2HPO
4And 0.24g KH
2PO
4, the pH to 7.4 with the HCl regulator solution adds water and is settled to 1L, at 15lbf/in2 (1.034 * 10
5Pa) vapor sterilization 20 minutes under the high pressure is stored in room temperature; HBS:(10mM Hepes, 100mM NaCl, pH8.0); Scintillation solution: (PPO 3.6g, POPOP 0.36g, dimethylbenzene 600ml, Triton X-100300ml).
2) determination step:
(1) prepare GABA transporter gene screening cell engineering cell strain by currently known methods:
The GABA transporter gene is the neurotransmitter transporter gene of cloning the earliest.Up to the present, cloned four kinds of GABA transporter genes, they belong to Na
+/ Cl
-Translocator family.
The GAT-1 gene clone is arrived on the suitable expression vector (pCDNA3) with the method transfection of cell transfecting, carrier is transferred in the eucaryon Chinese hamster ovary celI, by large quantities of cell cultures, be expressed in CHO (Chinese hamster oocyte) cell with making GAT-1 gene clone high expression level amount.By surveying isotropic substance picked-up flow and West blot (antibody response experiment) determining its expression amount and to determine whether to be target protein (GAT-1), thus the acquisition monoclonal cell.The GAT-1 monoclonal cell of determining is cultivated through passage cell, obtained large quantities of being used to and test the required screening cell engineering cell strain that contains the GAT-1 transporter gene.
(2) activity of mensuration GABA translocator:
In RMPI 1640 substratum that contain 10% calf serum, cultivate the D8 cell and be paved with (about every hole 60,000 cells) in 48 orifice plates (Costar) to flat board.Abandon training liquid, with PBS washing once, inhale and go PBS solution, every hole to add 90 μ l HBS, 25 ℃ of incubations 10 minutes, every hole adds 10 μ l HBS reaction solutions and (contains 50nM[
3H] GABA).25 ℃ of incubations 20 minutes, with the PBS solution washing of ice bath three times, with 100 μ l 2N NaOH solution cracking 30 minutes, the lysate of drawing each hole joined in the scintillation solution of 1.6ml, put into liquid and dodge the isotopic content of numeration instrument detection, measure activity＞100,000 DPM of GABA translocator.
(3) medicament screening experiment (SOP):
I. 48 inoculation culture is good porocyte plates upset fast get rid of the unnecessary nutrient solution of culture hole, and blot on thieving paper.
Ii. each culture hole is washed once with 1 * PBS, and upset fast discards PBS then, and button is done.
Iii. add HBS successively, the every hole 90 μ l of negative, positive control, the every hole of medicine group HBS+ medicine is totally 90 μ l, and room temperature was placed 10 minutes.
Iv. every hole adds the 10 μ l[that prepare in advance
3H] isotropic substance of mark, room temperature is placed 20 minutes (1 * PBS being placed-20 ℃ of refrigerators).
V. ice PBS and give a baby a bath on the third day after its birth time, and blot.
Vi. every hole adds 2N NaOH lysate 100 μ l, and room temperature was placed 20 minutes.
Vii. lysate sucking-off from each culture hole is also gone in the 2ml round bottom eppendorf pipe separately, every hole adds the 1.6ml scintillation solution, puts upside down mixing, in the 5ml pipe of packing into, is positioned on the liquid glimmer instrument and measures
3HDPM.
(4) preparation standard curve:
Experiment divides three groups: sum up set up jointly, non-specific combination group, standard model group.Every group of two multiple pipe or three multiple pipes.Measured amount is respectively: total binding, non-specific combination amount, the amount of recording.Total binding: the Chinese hamster ovary celI of transfection GABA transporter gene to [
3H]-GABA in conjunction with number (not dosing in conjunction with number); Non-specific combination amount: the Chinese hamster ovary celI of untransfected GABA transporter gene to [
3H]-GABA in conjunction with number; The amount of recording: the Chinese hamster ovary celI of the GABA of the transfection transporter gene after the dosing to [
3H]-GABA in conjunction with number.Total binding deducts non-specific combination amount and obtains the specific combination amount.
Can try to achieve the inhibiting rate of standard model by following formula: inhibiting rate (the %)=log[(amount of recording-non-specific combination amount)/(total binding-non-specific combination amount) to radio-labeled part and GABA translocator specific combination] * 100%
X=-logM M: concentration; Y=log specificity combination rate;-log (IC
50)=X (working as Y=log50).
With concentration-effect logarithm graphing method, is ordinate zou with specificity in conjunction with suppressing percentile log value, negative logarithm with standard model concentration is the X-coordinate mapping, gets the equation of linear regression of concentration and inhibiting rate relation, calculates specificity in conjunction with suppressing half desired concn IC
50
Table 1 is the pharmacologically active result of The compounds of this invention.
The result shows that The compounds of this invention has GAT-1 and suppresses active, and wherein compound 1 and 2 activity are all apparently higher than positive control (R)-nipecotic acid.
Table 1
| Compound number | 1 | 2 | 3 | (R)-nipecotic acid |
| IC 50(μM) | 84 | 123 | 3450 | 456 |
Claims (8)
1, the 1-benzyl tetrahydro isoquinoline compound of formula I,
Wherein, R
1=H or CH
3Or other alkyl;
R
2=H or CH
3Or other alkyl;
Wherein, Ar
1=phenyl or substituted-phenyl or fragrant heterocycle or replacement virtue heterocycle;
Ar
2=phenyl or substituted-phenyl or fragrant heterocycle or replacement virtue heterocycle;
R
3The alkyl side chain of=replacement.
2,1-benzyl tetrahydro isoquinoline compound according to claim 1, the compound that it is characterized in that having structure 1,
3,1-benzyl tetrahydro isoquinoline compound according to claim 1, the compound that it is characterized in that having structure 2,
4,1-benzyl tetrahydro isoquinoline compound according to claim 1, the compound that it is characterized in that having structure 3,
5, the preparation method of the described 1-benzyl tetrahydro isoquinoline compound of claim 1; it is characterized in that 1-benzyl tetrahydro isoquinoline parent nucleus is done structure of modification; comprise that N goes up the 1-benzyl tetrahydro isoquinoline compound of alkyl side chain or the replacement of N-acyl side-chain; and the 1-benzyl tetrahydro isoquinoline compound that the different alkoxyl group of introducing replaces on its phenyl ring; preparation process as shown in the formula
Route 1
Route 2
6, the purposes of the 1-benzyl tetrahydro isoquinoline compound of claim 1 in preparation GAT-1 inhibitor.
7, the purposes of the 1-benzyl tetrahydro isoquinoline compound of claim 1 in preparation treatment nervosa or psychotic disorder medicine.
8, the 1-benzyl tetrahydro isoquinoline compound of claim 1 is in preparation treatment epilepsy, anxiety, the purposes in chronic pain or the insomnia drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100264693A CN1312132C (en) | 2005-06-03 | 2005-06-03 | 1-benzyl tetrahydro isoquinoline compound, its preparing process and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100264693A CN1312132C (en) | 2005-06-03 | 2005-06-03 | 1-benzyl tetrahydro isoquinoline compound, its preparing process and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1721408A true CN1721408A (en) | 2006-01-18 |
| CN1312132C CN1312132C (en) | 2007-04-25 |
Family
ID=35912065
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100264693A Expired - Fee Related CN1312132C (en) | 2005-06-03 | 2005-06-03 | 1-benzyl tetrahydro isoquinoline compound, its preparing process and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1312132C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491945A (en) * | 2011-12-09 | 2012-06-13 | 南京威尔化工有限公司 | Method for recovering S-shaped tetrahydroisoquinoline |
| CN111303017A (en) * | 2019-08-28 | 2020-06-19 | 上海中医药大学 | Compound containing 9, 10-dihydrophenanthrene skeleton and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1246322C (en) * | 2003-01-21 | 2006-03-22 | 承德医学院中药研究所 | Dehydrogenation 'nudike' alkali and preparation method as well as preparation method for synthesizing 'nudike' alkali |
-
2005
- 2005-06-03 CN CNB2005100264693A patent/CN1312132C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491945A (en) * | 2011-12-09 | 2012-06-13 | 南京威尔化工有限公司 | Method for recovering S-shaped tetrahydroisoquinoline |
| CN111303017A (en) * | 2019-08-28 | 2020-06-19 | 上海中医药大学 | Compound containing 9, 10-dihydrophenanthrene skeleton and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1312132C (en) | 2007-04-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5330375B2 (en) | Pyrimidinones as casein kinase II (CK2) modulators | |
| JP2010531849A (en) | Imidazo [1,2-c] pyrimidin-2-ylmethylpiperidine derivatives as orexin receptor antagonists | |
| JP6851367B2 (en) | IRAK4 Inhibitors and Their Applications | |
| JP2009512692A (en) | Pyrimidiones as casein kinase II (CK2) modulators | |
| JPH05194477A (en) | Medicinal compound | |
| CN103965159A (en) | Ether aryl piperazine derivatives and salt thereof as well as preparation method and application of ether aryl piperazine derivatives | |
| CN104356099A (en) | Homoserine lactone compounds as well as preparation methods and application thereof | |
| CN101282965A (en) | Alkoxy indolinone based protein kinase inhibitors | |
| CN103450176A (en) | Naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and application thereof | |
| CN1721408A (en) | 1-benzyl tetrahydro isoquinoline compound, its preparing process and use thereof | |
| CN104910894B (en) | Benzimidazole hERG potassium ion channel small-molecular fluorescent probe and preparation method and applications thereof | |
| AU2021320763A1 (en) | Compositions for modulating splicing | |
| CN111518104B (en) | 1,2, 4-triazolo [1,5-a ] pyrimidine compound containing thiourea pyrimidine and preparation method and application thereof | |
| CN103130801A (en) | Substituted beta-carboline compound and preparation method thereof | |
| CN103641834B (en) | Pyrrolobenzodiazepines * compounds and its preparation method and application | |
| CN101243075A (en) | Novel 2,3-dihydroindole compounds | |
| CN101092415B (en) | Compound of new benzo heterocycle categories, preparation method and application | |
| CN100341871C (en) | Organic sulfur compound containing piperidine structure, its preparation and use | |
| CN101591357A (en) | One group is suppressed the kinase whose phosphate/phosphate ester compounds of BCR-ABL | |
| Minarini et al. | Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1, 2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics | |
| CN112624927B (en) | TRPV3 inhibitor and preparation method thereof | |
| CN1052481C (en) | Platelet activating factor antagonist and preparation thereof | |
| Fang et al. | Synthesis and Preliminary Anti‐leukemia Activity of N‐(Substituted Benzyl)‐4‐hydroxy‐4‐substituted Piperidine Derivatives | |
| CN102670617B (en) | Application of ibuprofen 2-(2-arylmorpholine-4-yl) ethyl ester in preparation of antidepressant drugs | |
| CN102675300A (en) | Lipoic acid-aporphine conjugated compound, medicine composite and usage thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070425 Termination date: 20100603 |