CN1456560A - 1-aryl beta-carboline and thio-similities, their preparations and uses in medicines - Google Patents
1-aryl beta-carboline and thio-similities, their preparations and uses in medicines Download PDFInfo
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Abstract
A 1-aryl beta-carboline and its thio-analog and its preparing process are disclosed. It can be used to prepare the medicine for treating senile dysmnesia, such as senile hypomnesia and Alzheimer disease. Its advantages are high curative effect and low toxic by-effect.
Description
Technical field:
The invention belongs to the synthetic field of medicine, be specifically related to 1-aryl 'Beta '-carboline compound and thip-analogues thereof, its preparation method and in pharmaceutically application.
Background technology:
Elderly population are increasing to be one of modern social development's trend, and the old number in the whole world in 2000 accounts for 9.9% of population, China more than 60 years old the old man reached more than 1.3 hundred million, account for total population 11%.Simultaneously, senile memory dysfunction diseases such as senile hypomnesis, senile dementia also more and more have a strong impact on the elderly's the quality of life and the life time limit.Alzheimer's disease (Alzheimer ' s disease, be called for short AD, claim senile dementia early again) and senile memory impairment are modal class cognitive disorder diseases.In developed country 1,200 ten thousand AD patients are arranged approximately, 5% in various degree senile memory dysfunction patient is arranged among the crowd more than 60 years old approximately on China Beijing, Shanghai and other places.Therefore senile memory dysfunction disease had become medical science that needs to be resolved hurrily and social concern already.
According to the study, senile dementia (AD) is a kind of neurodegenerative disease of unknown etiology, can cause pallium and hippocampus primary injury, causes that cortical neuron reduces, and makes the patient functional defect occur.In addition, the deterioration of neuron system such as cholinergic, dopaminergic, serotonin energy and norepinephrine under the cortex also makes the pallium damage increase the weight of.Biochemistry in AD patient's brain changes and shows as acetylcholinesterase (AChE) and cholinacetyltranslase (ChAT) level reduces, and to picked-up (HACU) ability drop of high-affinity choline, presynaptic cholinocepter reduced number, cerebral blood flow (CBF) reduction; Simultaneously, neurone reduces, and shows as amyloid patch and neurofibrillary tangles.According to the cholinergic hypothesis, cholinergic minimizing directly causes the damaged of cognitive and memory capability in AD patient's brain.
For this reason, be that the medicine of target can comprise AChE inhibitor, nicotine and malicious deep alkali M with the cholinergic system
1Receptor stimulant and ACh release enhancers.In addition, with regard to promoting that ACh discharges, can implement acceptor (adenosine, serotonin, histamine, TRH, malicious deep alkali, nicotine) for example, ionic channel (Ca by different mechanism
+ 2, K
+), metabolic regulating effect and broad variety such as bright mechanism not.Though cholinergic drug be research both at home and abroad early and more class treatment AD medicine, as the selagine of being developed by the Tacrine of drugs approved by FDA and China, its therapeutic index is not high.So highly effective senile memory dysfunction disease methods of treatment or medicine are not arranged so far as yet.Recent studies has shown that human learning and memory function is not only relevant with a neurotransmitter, at least relevant with brain various neurotransmitters acceptor (acceptors such as opium, NMDA, GABA, 5-HT) with ionic channel, therefore, strengthen brain function, improve learning and memory and treat the research of the generalization nootropics of senile memory dysfunction disease and seem very urgent and have Practical significance by different approaches.
Report is arranged, the tall and erect acceptor (BZR) of benzene a pair of horses going side by side phenodiazine, gamma-aminobutyric acid receptor A (GABA
A) and the chloride channel complex body on memory function, play an important role.Benzene a pair of horses going side by side diazepine medicine is present clinical widely used calming soporific, anxiety, medicine anticonvulsion and of flaccid muscles, but life-time service energy obvious damage man memory function, BZR and GABA
AThe equal tool of the agonist of acceptor is forgotten effect, has confirmed that the endogenous benzene a pair of horses going side by side phenodiazine Zhuo that discharges in (septum), amygdala (amygdala) and hippocampus (hippocampus) in the brain can activate GABA
AAcceptor, and open chloride channel, thereby to anxiety and/or memory function performance downward modulation effect under stress situation when tired.On the contrary, BZR antagonist such as Flumazenil or GABA
AReceptor antagonist such as MDL26479 (Suritozole) but the above-mentioned downward modulation effect of antagonism and improve memory function.Current abroad to BZ-GABA
AAcceptor research comprises that (1) selectivity improves BZ-GABA
ANeurotransmission, separating the various pharmacologically actives of classical BZ class medicine effectively, do not have calmness-hypnosis side effect, or anesthesia and do not have and forget side effect before can be used for performing the operation to produce the selectivity angst resistance effect, perhaps (2) selectivity reduces BZ-GABA
ANeurotransmission, strengthening understanding, vigilance, mnemonic learning function effectively, and do not cause side effects such as convulsions, anxiety, aggressive behaviour, be used for the treatment of senile memory dysfunction disease.
??????????????????????
Flunitrazepam：R＝NO
2，R
1＝Me，X＝O，R＝F???????????Flumazenil(Ro?15-1788)：
R
8＝F
Cause both at home and abroad special the attention at present, the BZR reversibility agonist-obvious antagonism BZ/GABA of 'Beta '-carboline compound tool acceptor is to the downward modulation effect of memory, as ZK93426 obviously in antagonism different animals model and the volunteer's test Scopolamine (SCOP) movement memory and cognitive detrimental effect are promoted ability of learning and memory.Other β-Ka Lin reversibility agonist such as β-CCM, β-CCB, FG7142 etc. all have the activity of promotion animal learning memory in various degree.
β-CCM∷R
3＝CO
2CH
3；β-CCB：R
3＝CO
2Bu-n；FG7142：R
3＝CONHCH
3；ZK93426：R
3＝CO
2Et，R
4＝CH
3，R
5＝OPr
-β-Carbolines(Inverse?agonist，Antagonist，etc)
Therefore, the reversibility agonist β-Ka Lin of BZR/GABA-A is considered to new lead compound structure in the nootropics research, wherein seek from the structure of modification of the beta-carboline alkaloid of natural radioactivity avoid it easily to cause excited side effect such as frightened, improve the specificity of memory function and easily absorb, the convenient novel β-Ka Lin class nootropics that uses is the very new drug research direction of meaning of a tool.
Bioisosteres?of?β-carbolines：[1]Benzothieno[2，3-c]pyridines：1：R
1＝R
2＝R
4＝H，R
3＝COOC
2H
52：R
1＝R
2＝R
4＝H，R
3＝CONH-Ch3：R
1，R
2?and?R
3，R
4＝double?binc???R
3＝CONHCH
2CH
2NH
2.HCl
The anti-attack that bioisostere-thionaphthene [2,3-c] pyridine of Kawakubo etc. report β-Ka Lin and tetrahydrochysene derivative tool thereof are good and improve the effect of memory impairment.Amino acid receptors such as γ-An Jidingsuan (GABA) and glycine also play the regulating effect of different loci in people's memory process in addition, improve the memory function activity as equal tool such as GABA antagonist, glycine prodrug milacemide (milacemide), NMDA/ Glycine Receptors agonist D-seromycin; Pyrrolidinone compounds thing: piracetam (piracetam, piracetam), the cyclisation derivative of aniracetam (aniracetam), naphthalene Fei Xitan γ-An Jidingsuans (GABA) such as (nefiracetam) already as the nootropics Application and Development in clinical, can be by regulating the release that calcium channel cause presynaptic nerve ending ACh; Pantoyl (Pentolyl) GABA also can promote the release of ACh.
???????????????Piracetam：R＝CH
2CONH
2???????????????Aniracetam：R＝COC
6H
4OCH
3-p???????????????Nefiracetam：R＝CH
2CONHC
6H
3Me
2-Pantolyl-GABA
Summary of the invention:
Technical problem to be solved by this invention provides novel 1-aryl 'Beta '-carboline compound and the thip-analogues thereof that a class selectivity is good and toxic side effect is low.
1-aryl 'Beta '-carboline compound of the present invention and thip-analogues thereof have the structure of formula I or II:
Wherein:
X=N, SR are H, halogen, and hydroxyl,
R ' is H, alkyl, alkoxyl group, hydroxyl, carboxyl, carboxylicesters, ketone group, acyl group, alkylsulfonyl and halogen.
R3 is carboxyl, carboxylicesters, ketone group, hydroxyl, acyl group, alkylsulfonyl, alkyl, alkoxyl group, halogen and aryl.
R4, R5, R6, R7 and R8 can be independently hydrogen, aryl, substituted aryl, alkyl, alkoxyl group, halogen, carboxyl, carboxylicesters, ketone group, hydroxyl, amide group or amido.
R9 can be a hydrogen, alkyl, cycloalkyl, aryl or substituted aryl, acyl group.
The compounds of this invention is by pharmacodynamics mouse water labyrinth direction identification service test research, toxicologic study (LD
50Test) and the reverse mutation test (Salmonella reversion test) of microorganism, show the active and less toxic side effect of good short intelligence, can further develop to treating the new drug of senile hypomnesis, senile dementia senile memory dysfunction diseases such as (Alzheimer diseases).
Preferred compounds of the invention are the compound of following 1,2,3,4 structures,
Preferred compound of the present invention studies confirm that by the service test of pharmacodynamics mouse water labyrinth direction identification significantly short intelligence activity is arranged.
Another technical problem to be solved by this invention is the preparation method who discloses above-mentioned novel 1-aryl 'Beta '-carboline compound and thip-analogues thereof.
1-aryl 'Beta '-carboline compound disclosed by the invention and thip-analogues thereof are raw material with tryptophane or benzene a pair of horses going side by side thiophene α-An Jibingsuan, adopt methods such as bionical Picter-Spengler cyclization and dehydrogenation oxidation to synthesize designed compound.Obtain by the following formula reaction,
X，Y＝NH，or?S，O
Wherein, R
1, R
2, R
3, R
4, R5, R6, R7, R8, R9 definition as mentioned above.
The embodiment of the invention 1 is described the preparation method of compound 2 in detail, the preparation process of this compound as shown in the formula:
The preparation method of compound 2 is: with tryptophane and 5-acetyl-o-methyl-2 furan carboxyaldehyde stirring at room 24 hours under methylene dichloride-trifluoracetic acid condition, after the evaporate to dryness washing compound 5 crude products.Compound 5 adds potassium permanganate oxidation after being dissolved in Glacial acetic acid in batches, and backflow 15min. pressure reducing and steaming solvent is with getting compound 6 after ether extraction, washing, the drying.Ester 6 is dissolved in methyl alcohol, pressure reducing and steaming solvent behind the adding strong aqua stirring at room 18h, the solid of gained uses column chromatography purifying and obtains compound 7.Add N-carbobenzoxy-(Cbz)-γ-An Jidingsuan, DCC, 4-Dimethylamino pyridine and CH in the alcohol 6
2Cl
2, stirring at room is filtered to reacting completely, and filtrate is water successively, 5%HOAc and water washing, anhydrous MgSO
4Drying is filtered the separation and purification of evaporate to dryness plate preparative chromatography and is obtained ester cpds 2.
Adopt essentially identical method, the embodiment of the invention 2,3,4 provides the preparation method of compound 3,1,4 respectively.
Another technical problem to be solved by this invention is to disclose above-mentioned novel 1-aryl 'Beta '-carboline compound and thip-analogues thereof in preparation with treat application in the medicine of senile hypomnesis, senile dementia senile memory dysfunction disease diseases related such as (Alzheimer diseases).
The present invention's novel 1-aryl 'Beta '-carboline compound and thip-analogues thereof show that by pharmacodynamic study (service test of mouse water labyrinth direction identification) result described compound can improve the mouse memory obstacle, and its intensity is similar to tacrine (the anti-degenerative brain disorder medicine of drugs approved by FDA) or slightly high.Toxicologic study (LD
50Test) result shows that The compounds of this invention and thip-analogues toxicity thereof are little, LD
50＞500mg/kg.The reverse mutation test of microorganism (Salmonella reversion test) shows its no mutagenesis.The result confirms, 1-aryl 'Beta '-carboline compound of the present invention and thip-analogues thereof have the active and less toxic side effect of significantly short intelligence, can prepare the new drug of the senile hypomnesis of treatment, senile dementia senile memory dysfunction diseases such as (Alzheimer diseases).
Embodiment:
Embodiment 1
Synthetic 1-[5 '-(N-carbobenzoxy-(Cbz)-ammonia butyroxymethyl)-furans-2 '] base-β-Ka Lin (compound 2)
1) ice bath cooling down to tryptophane (10.2g, 50mmol), 5-acetyl-o-methyl-2 furan carboxyaldehyde (11.8g, 70.2mmol) and anhydrous CH
2Cl
2Drip in the mixture (280ml) trifluoracetic acid (2ml, 82.2mmol).Gained liquid continues to stir 1.5h at ice bath, then at room temperature reaction 24h.Reaction finishes to boil off solvent on the Rotary Evaporators of back, the brown solid of gained ether (3 * 50ml) thorough washing.Obtain 1-(5 '-acetyl-o-methyl-furans-2 ') base-1,2,3 after the oven dry, the crude product of 4-tetrahydrochysene-β-Ka Lin-3-formic acid 5.The not purified the next step that is directly used in of this crude product.
2) will go up the compound 5 that goes on foot the reaction gained and be dissolved in Glacial acetic acid (675ml), oil bath backflow 5min adds KMnO in batches in 10min
4(10.2g, 64.6mmol).Add the back and continue backflow 15min. pressure reducing and steaming solvent, (3 * 500ml) fully extract the viscous fluid of gained with ether.United extraction liquid is with saturated NaCl solution (4 * 300ml) washings, anhydrous MgSO
4Drying is filtered, and boils off solvent and gets 1-(5 '-acetyl-o-methyl-furans-2 ') base-β-Ka Lin 6 (3.25g, two step yields 21%).
1H?NMR(CDCl
3，ppm)：δ9.93(brs，1H，N
9-H)，8.43(d，1H，J＝5.0，C
3-H)，8.13(d，1H，J＝8.0，C
5-H)，7.89(d，1H，J＝5.0，C
4-H)，7.69(d，1H，J＝8.0，C
8-H)，7.58(t，1H，J＝8.0，C
7-H)，7.29(t，1H，J＝8.0，C
6-H)，7.19(d，1H，J＝3.3，C
4’-H)，6.62(d，1H，J＝3.3，C
3’-H)，5.28(s，2H，CH
2)，2.17(t，3H，CH
3)；EIMS：m/z?306(M
+·，81.51％)，247(83.32％)，246(100％)，167(22.32％)。
3) (1169mg 3.82mmol) is dissolved in methyl alcohol (50ml), adds strong aqua (20ml), stirring at room 18h with ester 6.The pressure reducing and steaming solvent, the solid of gained column chromatography (elutriant: CHCl
3/ CH
3OH 10/1) separation and purification, obtain 1-(5 '-methylol-furans-2 ') base-β-Ka Lin 7 (854.2mg, 85%).
1H?NMR(CD
3COCD
3，ppm)：δ8.38(d，1H，J＝5.0，C
3-H)，8.24(d，1H，J＝8.0，C
5-H)，8.04(d，1H，J＝5.0，C
4-H)，7.76(d，1H，J＝8.0，C
8-H)，7.56(t，1H，J＝8.0，C
7-H)，7.28(t，1H，J＝8.0，C
6-H)，7.24(d，1H，J＝3.5，C
3’-H)，6.57(d，1H，J＝3.5，C
4’-H)，4.74(s，2H，CH
2)；EIMS：m/z?265(M
+·+1，24.80％)，264(M
+·，100％)，247(66.65％)，246(46.35％)，167(15.94％)。
4) in reaction flask, add N-carbobenzoxy-(Cbz)-γ-An Jidingsuan (10mmol), DCC (11.0mmol), alcohol 7 (11.0mmol), the 4-Dimethylamino pyridine (DMAP, 1mmol) and CH
2Cl
2(30ml).Stirring at room is to reacting completely. filter, filtrate successively water (3 * 50ml), 5%HOAc (3 * 50ml) and water (3 * 50ml) washings, anhydrous MgSO
4Drying is filtered, and evaporate to dryness is with plate preparative chromatography (CHCl
3: CH
3COCH
310: 1) separation and purification obtains 1-[5 '-(N-carbobenzoxy-(Cbz)-ammonia acetyl-o-methyl)-furans-2 '] base-β-Ka Lin 2.yield：35％；
1H?NMR(CDCl
3，ppm)：δ9.88(brs，1H，N
9-H)，8.38(d，1H，J＝5.0，C
3-H)，8.06(d，1H，J＝7.8，C
5-H)，7.80(d，1H，J＝5.0，C
4-H)，7.61(d，1H，J＝8.0，C
8-H)，7.45(t，1H，J＝8.0，C
7-H)，7.26~7.28(m，6H，C
6-H，ph-H)，7.16(d，1H，J＝3.0，C
3’-H)，6.58(d，1H，J＝3.0，C
4’-H)，5.49(brs，1H，N-H)，5.28(s，2H，CH
2)，5.02(s，2H，CH
2)，4.03(d，1H，J＝5.8，CH
2)；EIMS：m/z?455(M
+·，4.0％)，247(31.6％)，108(32.8％)，91(100％)。
Embodiment 2:
Synthetic 1-(5 '-propionyl oxygen methyl-furans-2 ') base-β-Ka Lin (compound 1)
Ice bath cooling adds propionyl chloride (0.71mmol) DMAP (or triethylamine, CH 0.71mmol) down
2Cl
2(10ml) in the solution, and adding alcohol 6 behind the stirring 1h (25mg, 0.095mmol).Remove ice bath, stirring at room is until reacting completely.Filter evaporate to dryness.Gained solid plate preparative chromatography (CHCl
3: CH
3COCH
310: 1) separation and purification and obtain 1-(5 '-propionyl oxygen methyl-furans-2 ') base-β-Ka Lin 1.yield：37％；
1H?NMR(CDCl
3，ppm)：δ10.00(brs，1H，N
9-H)，8.41(d，1H，J＝5.0，C
3-H)，8.11(d，1H，J＝8.0，C
5-H)，7.86(d，1H，J＝5.0，C
4-H)，7.69(d，1H，J＝8.0，C
8-H)，7.57(t，1H，J＝8.0，C
7-H)，7.27(t，1H，J＝8.0，C
6-H)，7.18(d，1H，J＝3.5，C
4’-H)，6.60(d，1H，J＝3.5，C
3’-H)，5.27(s，2H，CH
2)，2.44(q，2H，CH
2)，1.19(t，3H，CH
3)；EIMS：m/z?321(M
+·+1，30.08％)，320(M
+·，69.58％)，263(24.18％)，247(100％)，246(89.57％)。
Embodiment 3
Synthetic 1-[5 '-(N-carbobenzoxy-(Cbz)-ammonia acetyl-o-methyl)-furans-2 '] base-β-Ka Lin (compound 3)
In reaction flask, add N-carbobenzoxyglycine (10mmol), DCC (11.0mmol), alcohol 6 (11.0mmol), the 4-Dimethylamino pyridine (DMAP, 1mmol) and CH
2Cl
2(30ml). stirring at room is to reacting completely. filter, filtrate successively water (3 * 50ml), 5%HOAc (3 * 50ml) and water (3 * 50ml) washings, anhydrous MgSO4 drying is filtered, evaporate to dryness is with plate preparative chromatography (CHCl
3: CH
3COCH
310: 1) separation and purification obtains 1-[5 '-(N-carbobenzoxy-(Cbz)-ammonia acetyl-o-methyl)-furans-2 '] base-β-Ka Lin 3.yield：35％；
1H?NMR(CDCl
3，ppm)：δ9.88(brs，1H，N
9-H)，8.38(d，1H，J＝5.0，C
3-H)，8.06(d，1H，J＝7.8，C
5-H)，7.80(d，1H，J＝5.0，C
4-H)，7.61(d，1H，J＝8.0，C
8-H)，7.45(t，1H，J＝8.0，C
7-H)，7.26~7.28(m，6H，C
6-H，ph-H)，7.16(d，1H，J＝3.0，C
3’-H)，6.58(d，1H，J＝3.0，C
4’-H)，5.49(brs，1H，N-H)，5.28(s，2H，CH
2)，5.02(s，2H，CH
2)，4.03(d，1H，J＝5.8，CH
2)；EIMS：m/z?455(M
+·，4.0％)，247(31.6％)，108(32.8％)，91(100％)。
Embodiment 4
Synthetic 1-(4 '-methoxyl group)-phenyl-thionaphthene [2,3-c] Nicotinicum Acidum methyl esters (compound 4)
1) the ice bath cooling is down to alpha-amino group-thionaphthene-3-propionic acid (50mmol), aubepine (70.2mmol) and anhydrous CH
2Cl
2Drip in the mixture (280ml) trifluoracetic acid (2ml, 82.2mmol).Gained liquid continues to stir 1.5h at ice bath, then at room temperature reaction 24h.Reaction finishes to boil off solvent on the Rotary Evaporators of back, the brown solid of gained ether (3 * 50ml) thorough washing.Obtain 1-(4 '-methoxyl group)-phenyl-1,2,3 after the oven dry, the crude product of 4-tetrahydrochysene-thionaphthene [2,3-c] Nicotinicum Acidum.The not purified the next step that is directly used in of this crude product.
2) in the 50ml eggplant-shape bottle, add anhydrous methanol 10ml, 1-(4 '-methoxyl group)-phenyl-1,2,3,4-tetrahydrochysene-thionaphthene [2,3-c] Nicotinicum Acidums (2.3mmol), the ice-water bath cooling feeds dry hydrogen chloride gas down, and reaction solution is clarified gradually, has solid to separate out subsequently, remove ice-water bath, temperature rising reflux, reaction TLC (propyl carbinol/acetic acid/water, 5: 1: 1) follow the tracks of, stopped reaction after 6 hours boils off quantity of solvent, gets white solid.Inwardly add frozen water, regulate pH to 10 with 25% ammoniacal liquor then, get yellow muddy liquid, (5 * 10ml) extract, and merge faint yellow chloroform extracted solution, wash with water to neutrality with chloroform, anhydrous magnesium sulfate drying filters, and boils off chloroform, obtain yellow product 1-(4 '-methoxyl group)-phenyl-1,2,3,4-tetrahydrochysene-thionaphthene [2,3-c] the Nicotinicum Acidum methyl esters, yield 75.6%.
3) in the 50ml round-bottomed flask, add 1-(4 '-methoxyl group)-phenyl-1,2,3,4-tetrahydrochysene-thionaphthene [2,3-c] Nicotinicum Acidum methyl esters (0.87mmol), dimethylbenzene 10ml, 1,4-dioxane 10ml, sulphur (5.6mmol), magnetic agitation refluxed 4 days.5th, beginning in 6 days the time respectively add sulphur (2 * 2.5mmol), the stopped reaction after 6 days that refluxes, pressure reducing and steaming solvent.Separate with PTLC, developping agent is a chloroform: methyl alcohol=19: 1, and scrape and get the product colour band, use methanol-eluted fractions, filter the pressure reducing and steaming solvent, obtain faint yellow solid 1-(4 '-methoxyl group)-phenyl-thionaphthene [2,3-c] Nicotinicum Acidum methyl esters, yield is 50.4%.
1H?NMR(CDCl
3，ppm)：δ8.24-8.22(m，1H，C
5-H)，8.10-8.08(m，2H，C
2’，6，-H)，7.93-7.91(m，1H，C
8-H)，7.43-7.38(m，2H，C
6，7-H)，7.17(m，1H，C
4-H)，6.96-6.93(m，2H，C
3’，5’-H)，4.04-4.02(m，1H，-CH-)，3.78(s，3H，OCH
3)，3.66(s，3H，COOCH
3)，3.15(d，1H，CH
2)，2.97(d，1H，CH
2)。EIMS：m/z?272(M
+)。
The short intelligence activity experiment of embodiment 5 compounds
Measure pharmacodynamics governing principle-bureau of drug administration of the Ministry of Health that the experimental technique of the short intelligence activity of compound is formulated according to bureau of drug administration of the Ministry of Health: new drug preclinical study governing principle compilation pharmacy, pharmacology, toxicology, 1993 are P.47 ~ 50 described.Design water lost (Water maze): the record animal from the starting area arrive the target area required time and betwixt in the animal errors number that enters cecum, with these two indexs as the learning and memory achievement.Train once every day, and each 10 times, continuous 5 days.Table 1 is the improvement effect to mouse water labyrinth direction identification operative memory obstacle of The compounds of this invention and tacrine.
Table 1
Mean number ± SEM and physiological saline group be ##p＜0.01 conclusion relatively: test-compound can obviously improve the dysmnesia that Scopolamine produces, and 20mg/kg (i.p) and tacrine (the anti-degenerative brain disorder medicine of drugs approved by FDA) 20mg/kg (i.p) are in that to improve aspect the mouse memory obstructive action intensity similar.The toxicologic study of embodiment 6 compounds.
| Medicine | Dosage (mg/kg+mg/kg) Ip+ip | Number of animals (only) | The platform time (S) is supported in trip | Enter the cecum errors number |
| Physiological saline | ????/+/ | ????19 | ??9.94±0.69 | ??1.47±0.23 |
| Physiological saline+Scopolamine | ????/+5 | ????13 | ??37.46±6.53 ## | ??10.23±2.15 ## |
| Compound 2+Scopolamine | ????10+5 ????20+5 | ????12 ????12 | ??19.92±4.18 *??25.33±5.57 | ??3.83±1.06 *??5.75±1.95 |
| Compound 3+Scopolamine | ????20+5 ????40+5 | ????12 ????12 | ??20.08±5.51 *??33.25±5.43 | ??5.08±2.05 *??7.67±1.83 |
| Physiological saline | ????/+/ | ????12 | ??8.33±0.66 | ??0.58±0.26 |
| Physiological saline+Scopolamine | ????/+5 | ????16 | ??41.50±5.66 ## | ??9.13±1.51 ## |
| Tacrine+Scopolamine | ????10+5 ????20+5 ????30+5 | ????12 ????12 ????12 | ??26.50±5.49 ??19.5±4.46** ??27.5±5.87 | ??5.33±1.50 ? *1.91±0.63 **??4.33±1.21 ** |
LD
50Test: animal subject: Kunming mouse, abdominal injection are subjected to observe reaction of animals and death condition (week) behind the reagent thing.
Observe altogether a week after the administration, occur in after the administration the 2nd ~ 3 day mostly, individual animal is promptly observed the symptom that animal occurs death in the 5th day after the administration, and animal is originally for shakedown.Faint from fear stiff symptom before dead.Dead animal is not seen organs abnormality through dissecting.Toxicity of compound is little, LD
50＞500mg/kg.Table 2 is animal acute toxicity tests.
Table 2
| The animal dead number | |||||||||
| Dosage (mg/kg) | Number of animals (only) | Give death time (greatly) and dead animal number of elements approximately | General mortality rate (%) | ||||||
| ????1 | ??2 | ??3 | ??4 | ????5 | ????6 | 7 (my god) | |||
| ??800 | ????10 | ??7 | ????100 | ||||||
| ??680 | ????10 | ??6 | ??3 | ????70 | |||||
| ??578 | ????10 | ??3 | ??1 | ??1 | ????40 | ||||
| ??491.3 | ????10 | ????1 | ????10 | ||||||
The microorganism reverse mutation test (Salmonella reversion test) of embodiment 7 compounds.
1) negative control DMSO; Positive control is selected the generally acknowledged material that mutagenesis is arranged for use: disactivation (does not add S
9) person TA102 MMS, TA100 SA, TA98 be with 2,7-2AF, and TA97 9A; Activation (adds S
9) person TA
102, TA
100, TA
98And TA
97All use 2-AF.
2) bacterial strain adopts mouse typhus Salmonella histidine defect type mutant strain TA
102, TA
100, TA
98, TA
97, TA
102And TA
100Be used to detect the displaced type transgenation, TA
98And TA
97Be used to detect the frame shift type transgenation, bacterial strain is provided by California, USA university Salmonella reversion test chamber, is stored in-80 ℃ of refrigerators, all through the four step rule accreditation.
3) will be tried thing and be made into 100ug/ml by the concentration principle of successively decreasing with dimethyl sulfoxide (DMSO), 1mg/ml, 5mg/ml, five concentration of 10mg/ml and 50mg/ml, every ware adds 0.1ml during experiment.
4) rat liver homogenate microsomal enzyme system (S9) is induced by polychlorobiphenyl (Aroclor 1254), and-80 ℃ of cryogenic refrigerators are preserved.Measure its vigor with BaP or 2-AF during use.
5) experiment employing standard plate infiltration method, each is tried concentration and is made three parallel plates, and each plate adds and is subjected to test solution 0.1ml, and 37 ℃ of incubators are cultivated after 48 hours with Automatic Colony Counter counting bacterium colony, and each test repeats once.
6) result: the compound that tries of all concentration does not all have mutagenesis.
Table 3, the 4th, Salmonella reversion test result (1) (2).
3＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝SAM/CON TA100+S9 TA100-S9 TA98+S9 TA98-S9--------------------------------------------------------------------------------------------------------------------------DMSO 126.7±5.1 115.7±11.4 35.0±3.6 26.3±3.125000 124.3±4.5 120.7±2.1 34.0±5.6 36.0±2.01000 123.3±3.5 116.3±2.1 36.7±2.1 37.7±4.0500 126.7±6.5 119.7±5.5 53.0±4.0 50.3±2.5100 120.3±3.2 117.7±2.1 38.7±4.7 43.3±3.510 124.3±4.0 116.0±7.5 34.3±4.2 33.3±1.5SA1.00---807.7±33.5**------2-AF10.00 852.3±19.4**---677.0±51.1**---2,7-2AF100.00---------665.7±21.9**＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝
-
*：＞＝2*C **：＞＝3*C ( X±S ) 4＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝SAM/CON TA102+S9 TA102-S9 TA97+S9 TA97-S9------------------------------------------------------------------------------------------------------------------------------DMSO 272.7±10.6 225.0±7.9 133.0±7.5 122.7±3.525000 266.3±6.1 218.0±2.0 139.0±7.2 129.0±3.01000 273.3±6.7 218.3±6.1 124.7±3.5 119.7±3.1500 283.0±9.2 235.0±9.5 136.0±3.6 125.7±2.5100 267.3±4.0 222.0±4.6 121.3±4.5 116.7±3.510 265.3±10.0 222.7±6.4 120.7±3.1 120.7±2.1MMS4.00---832.7±36.9**------2-AF10.00 929.3±41.0**---819.3±49.1**---9A50.00---------804.3±82.5**＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝
*：＞＝2*C????????**：＞＝3*C????????????????????????????????????????????????????????????????????????????????????(X±S)
Claims (8)
1,1-aryl β-Ka Lin and thip-analogues thereof is characterized in that having the structure of formula I or formula II,
Wherein:
X＝N，S
R is H, halogen, and hydroxyl,
R ' is H, alkyl, alkoxyl group, hydroxyl, carboxyl, carboxylicesters, ketone group, acyl group, alkylsulfonyl and halogen.
R3 is carboxyl, carboxylicesters, ketone group, hydroxyl, acyl group, alkylsulfonyl, alkyl, alkoxyl group, halogen and aryl.
R4, R5, R6, R7 and R8 can be independently hydrogen, aryl, substituted aryl, alkyl, alkoxyl group, halogen, carboxyl, carboxylicesters, ketone group, hydroxyl, amide group or amido.
R9 can be a hydrogen, alkyl, cycloalkyl, aryl or substituted aryl, acyl group.
2,1-aryl β-Ka Lin according to claim 1 and thip-analogues thereof is characterized in that described compound has following structural,
3, the 1-aryl β-Ka Lin of claim 1 and the preparation method of thip-analogues thereof is characterized in that with tryptophane or benzene a pair of horses going side by side thiophene α-An Jibingsuan be raw material, adopt bionical Picter-Spengler cyclization and dehydrogenation oxidation method to synthesize described compound.
4, according to the preparation method of claim 3, undertaken by following preparation process,
X, Y=NH, or S, O wherein, R
1, R
2, R
3, R
4, R5, R6, R7, R8, R9 definition with claim 1.
5, the 1-aryl β-Ka Lin of claim 1 and thip-analogues thereof the purposes in the medicine of preparation treatment memory dysfunction disease.
6, the 1-aryl β-Ka Lin of claim 1 and thip-analogues thereof the purposes in the medicine of the senile memory dysfunction disease of preparation treatment.
7, the 1-aryl β-Ka Lin of claim 1 and thip-analogues thereof the purposes in the medicine of preparation treatment senile dementia disease (Alzheimer disease).
8, the 1-aryl β-Ka Lin of claim 1 and thip-analogues thereof the purposes in the short active medicine of intelligence of preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104003987A (en) * | 2014-06-03 | 2014-08-27 | 中国药科大学 | Tacrine-beta-carboline conjoined multifunction cholinesterase inhibitor |
| CN107652285A (en) * | 2017-10-17 | 2018-02-02 | 中国科学院昆明植物研究所 | A kind of Sirt1 activators containing perlolyrine and its preparation method and application |
| CN108409738A (en) * | 2017-02-10 | 2018-08-17 | 华东理工大学 | 3,4- methylenedioxyphenyls substituted-tetrahydro-B-carboline piperazinedione analog derivative and application thereof |
-
2003
- 2003-05-26 CN CN 03128873 patent/CN1253453C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104003987A (en) * | 2014-06-03 | 2014-08-27 | 中国药科大学 | Tacrine-beta-carboline conjoined multifunction cholinesterase inhibitor |
| CN104003987B (en) * | 2014-06-03 | 2016-03-23 | 中国药科大学 | The multi-functional anticholinesterase of the different two disjunctor class of tacrine-β-carboline |
| CN108409738A (en) * | 2017-02-10 | 2018-08-17 | 华东理工大学 | 3,4- methylenedioxyphenyls substituted-tetrahydro-B-carboline piperazinedione analog derivative and application thereof |
| CN108409738B (en) * | 2017-02-10 | 2020-10-16 | 华东理工大学 | 3, 4-methylenedioxyphenyl substituted tetrahydro-beta-carboline piperazine diketone derivative and application thereof |
| CN107652285A (en) * | 2017-10-17 | 2018-02-02 | 中国科学院昆明植物研究所 | A kind of Sirt1 activators containing perlolyrine and its preparation method and application |
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