CN1821243B - Substituted pyridine M1 receptor excitomotor, its preparing process and its use - Google Patents
Substituted pyridine M1 receptor excitomotor, its preparing process and its use Download PDFInfo
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Abstract
The present invention relates to a kind of substituted pyridine M1 receptor excitomotor and its preparation process and use in preparing medicine for M1 receptor, especially in preparing medicine for treating Alzheimer disease, strengthening learning and memory function, improving cognitive function, promoting intelligence growth and protecting nerve.
Description
Technical field
The present invention relates to a kind of pyridines M of replacement
1Receptor stimulant, its preparation method and be used for exciting M in preparation
1Purposes in the medicine of acceptor, particularly be used for the treatment of Alzheimer's disease in preparation, strengthen learning and Memory function, improve the purposes in the relevant medicine of cognitive function, short intelligence, neuroprotective.
Background technology
Senile dementia Alzheimer type disease (Alzheimer ' s disease, AD) be a kind of degenerative disease that damages the central nervous system that is main clinical manifestation with carrying out property cognitive disorder and memory.
The pathogeny of AD is multifactor and relates to a plurality of systems, thereby the target spot of medicine also is diversification.Based on pathogeny, the medicine of AD mainly is divided into cerebrovascular circulation activator, brain energy metabolism agent, cranial nerve propagation function activator, cranial nerve somatomedin, anti-apoptotic agent, oxidation inhibitor, anti--starch protein agent etc.
In the field of treatment AD, M
1The research of receptor stimulant is risen, because discover the hypotype M of M-ChR (Muscarinic receptors)
1Acceptor has substantial connection with the pathogeny of following four kinds of AD at least: the first, and (acetylcholine Ach) is a kind of neurotransmitter of remembering of promoting, critical functions such as its participation in learning, memory to vagusstoff., presynaptic cholinocepter destroyed when cholinergic neuron reduces, when cerebral blood flow (CBF) reduces, AD can take place.From the cholinergic angle, prevention and treatment AD, can be by following three kinds of methods: the 1. activity of acetylcholine esterase inhibition (acetyl cholinesterase AchE) makes the decomposition reduction of Ach; 2. increase the synthetic and release of Ach, its concentration is increased; 3. activate cholinocepter.At present AD research major part is concentrated on the acetylcholinesterase depressant (AchEI).Yet because the curative effect of AchEI depends on the integrated degree of cholinergic neuron, and patient's AD cholinergic neuron is damaged, and the neurone that can discharge vagusstoff constantly reduces, and the curative effect of AchEI is progressively reduced.[people such as Avery E E, Drugs Aging 1997,11:450] patient's AD postsynaptic membrane M on the other hand, according to the study
1The number of variations of acceptor is little.So different with AchEI is: if direct exciting M
1Acceptor can not only obviously improve symptom, and can delay the development of the course of disease, i.e. M
1Acceptor can improve the regression of cholinergic nerve system in the brain.In this sense, activate M
1Acceptor can prevent the generation of AD, therefore has the better development prospect than AchEI method on prevention and treatment AD.The second, one of pathogeny of AD is to occur a large amount of-amyloid (amyloid protein, A) precipitation and produce neurotoxic effect in the brain.Amyloid is that (amyloid precursor protein, APP) hydrolysis generates through-amyloid precursor protein.M
1Acceptor can be regulated metabolism [people such as Delapp N, the Biochem Biophys ResCommun.1998 Mar 6 of APP; 244 (1): 156], reduce the generation of APP, therefore have the effect that prevention AD takes place.The 3rd, the excessive phosphorylation of patient's AD Protein tau forms duplex filament (PHF), and finally forms neurofibrillary tangles (NFT) in cell, produce cytotoxicity.This also is one of important pathological characters of AD.Genis I finds [people such as Genis I, JNeurochem, 1996; 66 (2): 877] M
1Receptor stimulant can reduce the excessive phosphorylation of ApoE gene defect mouse Protein tau specifically, and the protein phosphorylation of normal mouse is not then had influence, and this illustrates M
1Acceptor has good selective action to treatment AD.The 4th, neurone is not recoverable, and apoptosis in neuronal is the major reason that AD takes place.And the factor of apoptosis is very complicated, such as, the shortage of neurotrophic factor and excessive A precipitation make neurone increase the susceptibility of damage, cause a large amount of neuron losses.M
1Acceptor can be regulated endogenous nerve growth factor subfunction, suppresses Neuron Apoptosis people such as [, Acta Neurol Scand, 1996,165 (suppl): s1] Wilcock GK, and this will play a key role to treatment and the prevention of AD.
In sum, M
1Acceptor is a very important target spot in prevention and treatment AD, it can improve the regression of cholinergic nerve system in the brain, regulate the metabolism of amyloid precursor protein, reduce the excessive phosphorylation of Protein tau, regulate the function of endogenous nerve growth factor, suppress Neuron Apoptosis, integrate prevention, treatment AD, so M
1Receptor stimulant has good development prospect.Therefore, the present invention selects the hypotype M of M-ChR (Muscarinic receptors)
1Acceptor is as the target spot of research.
The M that has the research prospect at present
1Receptor stimulant is also few, and is wherein outstanding to account for Nuo Meilin (Xanomeline, compound 1) people such as [, Mol Pharmacol 1998,53 (6): 1120] Cbristopoulos A.Its activity is stronger, with [
3H] Pz is that M1 agonist activity model is measured, it is to M
1The exciting dosage of acceptor is people such as 0.006nM[Harian E, and J.Pharmacol.EXP.Ther 1994,269:282].And its side effect is than non-selective and part selectivity M
1Receptor stimulant is little, again can with M
1Acceptor forms long combination, tool long-acting [people such as Christopoulos A, J Pharmacol Exp Ther.1999Jun; 289 (3): 1220].Along with the progress of aging population, more and more to the pharmaceutical requirements of geriatric disease, and the present clinical M1 receptor stimulant quantity of using is few, thus need the exploitation M1 receptor stimulant that more activity are higher or selectivity is stronger, to satisfy the medication of different crowd.
People such as Per Sauerberg think and [people such as Per Sauerberg, Bioorganic andmedicinal chemistry letters, 8, (1998) 2897-2902] introduce alkynyl in 3 side chains of compound 1 thiadiazoles ring, can make compound to M
1The bonding force of acceptor can further strengthen.
United States Patent (USP) [people such as Jeppesen, US 6,015,813, (2000)] is introduced alkynyl in 3 side chains, synthesized a series of 1,2,5-thiadiazole M
1Receptor stimulant (general formula I V is as follows), and find that compound IV is M completely
1Agonist, no M
2Agonist activity.But, the starting raw material of this compound is that different dicyclo, trinucleated nitrogen heterocyclics replaces formaldehyde, all can't buy, and can only oneself synthesize, and the result of retrieval CA shows to have only a kind of aldehyde to record synthetic method in these heterocycles in CA, and the synthetic method of all the other aldehyde all can't be found.The results list of retrieval CA is as follows:
Note 1: reference (Heterocycles, 24 (4), 971-7; 1986)
This shows that the synthetic quite difficulty of compound IV needs a kind of synthetic easily, active equal or higher M
1Receptor stimulant.
Summary of the invention
The technical problem to be solved in the present invention provides the compound and the salt thereof of a kind of general formula (I):
Wherein Z is O or S; X is O or S or C; R is that 2～6 of phenyl ring are gone up single positions or a plurality of locational substituting group, and it is respectively: H, F, Cl, Br, I ,-alkyl of COOH, 1～3 C, the alkoxyl group of 1～3 C ,-NH
2, CH
3CONH-, CH
3NH-, C
2H
5NH-, (CH
3)
2N-, (C
2H
5)
2N-,-C ≡ CH
3,-C=CH2.
Another technical problem that the present invention will solve provides the compound and the salt thereof of a kind of following general formula (II):
Wherein Z is O or S; X is O or S or C; R is that 2～6 of phenyl ring are gone up single positions or a plurality of locational substituting group, and it is respectively: H, F, Cl, Br, I ,-alkyl of COOH, 1～3 C, the alkoxyl group of 1～3 C ,-NH
2, CH
3CONH-, CH
3NH-, C
2H
5NH-, (CH
3)
2N-, (C
2H
5)
2N-,-C ≡ CH
3,-C=CH2.
Another technical problem that the present invention will solve provides the compound and the salt thereof of a kind of following general formula (III):
Wherein Z is O or S; X is O or S or C; R is that 2～6 of phenyl ring are gone up single positions or a plurality of locational substituting group, and it is respectively: H, F, Cl, Br, I ,-alkyl of COOH, 1～3 C, the alkoxyl group of 1～3 C ,-NH
2, CH
3CONH-, CH
3NH-, C
2H
5NH-, (CH
3)
2N-, (C
2H
5)
2N-,-C ≡ CH
3,-C=CH2.
Another technical problem that the present invention will solve provides general formula and is the compound of (I)-(III) and the preparation method of salt thereof, may further comprise the steps: (1) is starting raw material with the 3-pyridylaldehyde, generate 3-(3-sulfydryl-1,2,5-thiadiazoles-4-yl) pyridine through three-step reaction; Be raw material perhaps, generate 3-(3-chloro-1,2,5-oxygen diazole-4-yl) pyridine through three-step reaction with 3-pyridine acetonitrile;
(2) be raw material and propiolic alcohol condensation with the replacement iodobenzene of each described R among the claim 1-3 and generate the propine methanesulfonates of R substituted benzene with the Methanesulfonyl chloride esterification;
(3) product that obtains in step (1) and (2) is reacted the compound that generates general formula I, methylate through methyl iodide again, obtain the compound that general formula is II, through NaBH
4The reduction, and with all kinds of sour salifies, obtain the salt that general formula is the compound of III.
Another technical problem that the present invention will solve provides general formula and is used for exciting M for the compound and the salt thereof of (I)-(III) in preparation
1Application in the medicine of acceptor.
The pyridines M of new replacement of the present invention
1Receptor stimulant is the compound and the salt thereof of general formula (I)-(III)
Z is O or S in the above-claimed cpd; X is O or S or C; R is that 2～6 of phenyl ring are gone up single positions or a plurality of locational substituting group, and it is respectively: H, F, Cl, Br, I ,-alkyl of COOH, 1～3 C, the alkoxyl group of 1～3 C ,-NH
2, CH
3CONH-, CH
3NH-, C
2H
5NH-, (CH
3)
2N-, (C
2H
5)
2N-,-C ≡ CH
3,-C=CH2.
General formula I of the present invention, II, III compound preferably wherein Z be: S; X is: S; R is: H, F, Cl, Br, I ,-CH
3,-C
2H
5-OCH
3,-OC
2H
5,-NH
2, CH
3CONH-, CH
3NH-, C
2H
5NH-, (CH
3)
2N-, (C
2H
5)
2N-.Most preferred general formula I of the present invention, II, III compound are that wherein Z is: S; X is: S; R is: H, F, Cl, Br, I.
The salt of general formula I of the present invention, II, III compound is oxalate, hydrochloride, vitriol.
The preparation method of general formula I of the present invention, II, III compound and salt thereof is made up of step once:
(1) is starting raw material with the 3-pyridylaldehyde, generates 3-(3-sulfydryl-1,2,5-thiadiazoles-4-yl) pyridine through three-step reaction; Be raw material perhaps, generate 3-(3-chloro-1,2,5-oxygen diazole-4-yl) pyridine through three-step reaction with 3-pyridine acetonitrile;
(2) be raw material and propiolic alcohol condensation with the replacement iodobenzene of each described R among the claim 1-3 and generate the propine methanesulfonates of R substituted benzene with the Methanesulfonyl chloride esterification;
(3) product that obtains in step (1) and (2) is reacted the compound that generates general formula I, methylate through methyl iodide again, obtain the compound that general formula is II, through NaBH
4The reduction, and with all kinds of sour salifies, obtain the salt that general formula is the compound of III.
Activity test finds, the application in the medicine that general formula I, II, III compound all have function that the M1 agonist activity can be used for treating Alzheimer's disease, strengthen learning and Memory, improve cognitive function, short intelligence, neuroprotective are relevant.
People's such as the application's compound and Jeppesen 6,015, compound in No. 813 United States Patent (USP)s structurally is differentiated, and 4 substituting group is the compound of azabicyclic among the general formula I V, does not comprise the application's book institute synthetic pyridine and partially hydrogenated pyridine structure.
And the application's compound is compared with United States Patent (USP), with M
1The binding ability of acceptor is stronger.This conclusion has the support of theoretical support and experimental data.
Basis is to this type of M at first, theoretically
1The structure activity relationship of receptor stimulant (relation of structure and drug effect) is discovered, nitrogen and M among nitrogen on the Compound I pyridine heterocycle or the general formula I V on the aza heterocycle
1During receptor acting and acceptor form hydrogen bond, this hydrogen bond can play the effect that nitrogen on the thiadiazoles of location and acceptor form another hydrogen bond.
By to M
1Receptor structure discovers that it is that the ring rigidity is big more that heterocyclic is required, and volume is more little, and electric density is concentrated more, to M
1The agonist activity of acceptor good more (John S.Ward, J.Med.Chem.1995,38,3469-3481.).And aza is respectively in the compound formula in 6,015, No. 813 United States Patent (USP)s of people such as Jeppesen:
The aza heterocycle that is the compound of general formula I V is compared with the application's heterocycle N-methyl tetrahydro pyridine ring (THP), and volume is bigger, and electric density is disperseed, unfavorable and M
1The combination of acceptor (activity data is relatively seen below).Therefore the THP ring is in a ratio of optimized nitrogen heterocyclic ring with these heterocycles.
Secondly, compound of the present invention is compared with United States Patent (USP), to M
1The intrinsic activity of acceptor is stronger.
At present to M
1The agonist activity of acceptor multiple measuring method arranged.Usual earlier adopts the radioligand method, and the aglucon with radionuclide (as tritium) mark m receptor carries out specific association reaction with the corresponding M acceptor, thereby m receptor is carried out qualitative and quantitative analysis.Aglucon commonly used be [
3H] QNB and [
3H] PZ (Pirenzepine, pirenzepine).The compound that the application relates to adopts the new activity determination method that directly acts on acceptor at present, is called for short gene approach, is to utilize poisonous fungus choline M
1(this cell strain is expressed poisonous fungus choline M to the reporter gene cell strain of acceptor simultaneously
1The expression plasmid of acceptor and response element 3 * MRE/CRE/SRE/ luciferase reporter gene) whether detection compound has the poisonous fungus of activation choline M
1The intrinsic activity of acceptor.
After in this cell model, adding the compound that will test, have active compound can activated membrane on poisonous fungus choline M
1Acceptor, transmission by signal in a series of cells, the content of second messenger in the cell is changed, response element is experienced the content of second messenger in the born of the same parents, activate the great expression of luciferase reporter gene, add the photon number that is sent behind the luciferase substrate by reading, thereby detect the height of the expression amount of luciferase, judge the size of this compound vigor indirectly.When the different concns of same compound carries out determination of activity, cell has the luciferase expression of concentration dependent, compound can activating cells produces the highest luciferase expression be called as the peak response value, 50% needed compound concentration of peak response value is the EC of this compound
50If this compound can not activate the expression of luciferase, then this compound does not have activation M
1The intrinsic activity of acceptor, its response value and blank are close.Blank is that not have compound to add fashionable, the basic response value that cell itself has.
The detailed process of experiment is: (Gibico USA) collects M with the DMEM substratum that contains 3% foetal calf serum
1Cell strain, (Corning, USA), density is every hole 4 * 10 to be inoculated in 96 orifice plates by the amount of every hole 100 microlitres
4Individual, overnight incubation, every then hole adds 11 microlitres sample to be detected, cultivated 7 hours, the luciferase substrate B right-Glo (Promega that volume is equal in adding and the hole, USA), use the high flux screening analyzing and testing Analyst HT of system (Molecular Devices, the luminescence mode reads number of winning the confidence USA).
Blank (Basical control): (Gibico USA) collects the M1 cell strain, and (Corning, USA), density is every hole 4 * 10 to be inoculated in 96 orifice plates by the amount of every hole 100 microlitres with the DMEM substratum that contains 3% foetal calf serum
4Individual, put into CO2 incubator overnight incubation, added the DMEM substratum that 11 microlitres contain 3% foetal calf serum in every hole in second day, in CO
2Cultivate after 7 hours in the incubator and take out, the luciferase substrate B right-Glo that volume is equal in adding and the hole (Promega, USA), mixing, use the high flux screening analyzing and testing Analyst HT of system (Molecular Devices, the luminescence mode reads number of winning the confidence USA).
Relatively to M
1The agonist activity of acceptor has two main indexes, continues to increase concentration or dosage and the dosage of effect quantity when no longer continuing to rise with being meant of representing of peak response wherein, the intrinsic activity of reflection medicine.And EC
50Value representation such as can cause at the relative concentration or the dosage of validity response, the avidity of reflection medicine and acceptor, and it is big more that it is worth more little then intensity.
Because different methods surveys active experimental model difference, can't carry out direct specific activity, the contriver has sought compound 1 (be Xanomeline, account for Nuo Meilin) that radioligand method and gene approach all relate to as the intermediary object of reference, carries out specific activity.
Table 1 is the M of compound
1Commonly used when receptor agonist activity measurement result, the compound 1,2,3 in the table are respectively present various countries experimental determination M1 receptor agonist activities have a M
1The positive control of receptor agonist activity (compound 1 is Xanomeline, the 2nd, and Aceclidine, the 3rd, Arecoline).Compound 14-20 is the compound for preparing in the embodiment of the present application.
Because the IC in two sets of data
50Value is expressed the agonist activity to acceptor, the IC of different models
50Value can't be carried out the comparison of multiple, and %PI (efficacy) value representation that provides in the table 1 in 6,015, No. 813 United States Patent (USP)s of people such as Jeppesen is the intrinsic activity of compound, is to M
1The very important measurement index of receptor active.Peak response value in the application's the table 1 is expressed identical intension with the %PI (efficacy) that provides in 6,015, No. 813 United States Patent (USP) tables 1 of people such as Jeppesen, all represents the intrinsic activity to acceptor.Document (Lone Jeppesen, J.Med.Chem.1999.42.1999-2006) the 2002nd page, the peak response value that has provided control compound Xanomeline among the Table1 is 65.6, other aza heterogeneous ring compounds are (promptly with 6, the identical compound of compound structure in 015, No. 813 United States Patent (USP)) peak response value scope is between 57-108.Promptly and the ratio of the peak response value of middle object of reference Xanomeline between 0.86-1.69.In other words, even the strongest compound of intrinsic activity is only strong 1.69 times than Xanomeline.Yet clearly visible from the application's table 1: the peak response of middle object of reference compound 1 (accounting for Nuo Meilin) is 2.82, and the peak response value of all compounds is all greater than control compound, for the 2.09-3.42 of control compound doubly.Be far longer than 6,015, No. 813 compounds in the United States Patent (USP) intrinsic activity to acceptor.
That is, compare with compound 1, the compound 14,15,16,17,19,20,21,22 of embodiment of the invention preparation has stronger activation poisonous fungus choline M
1The intrinsic activity of acceptor and the affinity stronger than compound.
Table 1: the M1 receptor agonist activity measurement result of compound
Peak response multiple: the ratio of the maximum value of compound activating cells and Basical control (being the numerical value of cell when not being activated).
So the compound in compound of the present invention and 6,015, No. 813 United States Patent (USP)s relatively, to M
1The intrinsic activity of acceptor is stronger.And the intrinsic activity of compound of the present invention and all surpass the compound 1 that has clinical experiment at present with the affinity of acceptor.
In addition, compound of the present invention is simple in structure, synthetic more convenient.The difference of existing compound maximum is that heterocyclic stem nucleus are different in compound of the present invention and the prior art, and different heterocyclic stem nucleus are starting raw materials of whole piece synthetic route.The starting raw material of compound of the present invention is the 3-pyridylaldehyde, and this compound can be easy to buy in each big reagent company, and the price of chemistry alcohol is about 120$/250g.And 6,015, the structure of the compound of No. 813 United States Patent (USP)s is that Azabicyclic compounds and intramolecularly have chiral centre (structure is seen general formula I V), compare with the application's heterocycle N-methyl tetrahydro pyridine ring (THP), volume is bigger, raw material is not easy to obtain, and carry out asymmetric synthesis, has increased synthetic difficulty.
The synthetic route of compound of the present invention
Reaction scheme 1:
(i)KCN，THF，NH
4Cl，NH
3(ii)S
2Cl
2，DMF(iii)NaSH，CH
3OH
Reaction scheme 2:
(i)(PPh
3)
2PdCl
2，CuI，Et
2NH(ii)CH
3SO
2Cl，CH
2Cl
2
Reaction scheme 3:
(i)K
2CO
3，THF(ii)CH
3I，acetone(iii)NaBH
4，CH
3OH(iv)H
2C
2O
4，acetone
Wherein when R=H, be respectively compound 14,15,16
During R=Cl, be respectively compound 17,18,19
During R=F, be respectively compound 20,21,22
Embodiment 1
3-(3-(3-phenyl-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl)-1,2,5, the preparation of 6-tetrahydrochysene-1-picoline oxalate (compound 14)
With 7.089g (21.8mmol) 3-(3-(3-phenyl)-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl)-methanol solution of 1-picoline is positioned over during-10 ℃ of cryosels bathe, and adds 2.48g (65.5mmol) NaBH
4, stirred 1.5 hours, stopped reaction, methanol solvate is revolved in decompression, residue orange sticky solid.Use column chromatography, can obtain white crystal 3-(3-(3-phenyl-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl)-1,2,5,6-tetrahydrochysene-1-picoline.
1H-NMR(CDCl
3，300MHz)：δ7.28-7.43(5H，m)，δ6.07(1H，d，J＝2.1)，δ4.29(2H，s)，δ3.46(2H，d，J＝1.8)，δ2.62(2H，t，J＝5.48)，δ2.50(2H，m)，δ2.47(3H，s)。With 3-(3-(3-phenyl-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl)-1,2,5,6-tetrahydrochysene-1-picoline is dissolved in acetone, with the oxalic acid salify, can obtain 3-(3-(3-phenyl-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl)-1,2,5,6-tetrahydrochysene-1-picoline oxalate.
1H-NMR(CDCl
3，300MHz)：δ7.28-7.43(5H，m)，δ6.07(1H，d，J＝2.1)，δ4.29(2H，s)，δ3.46(2H，d，J＝1.8)，δ2.62(2H，t，J＝5.48)，δ2.50(2H，m)，δ2.47(3H，s)。
Embodiment 2
With 3-{3-(3-(3-chloro-phenyl-)-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl }-the 1-picoline is a raw material, compound 17 synthetic with similar approach.
1H-NMR(CDCl
3，300MHz)：δ7.19-7.40(4H，m)，δ6.72(1H，t，J＝2.1)，δ4.27(2H，s)，δ3.46(2H，d，J＝1.8)，δ3.52(2H，s)，δ2.68(2H，t，J＝5.4)，δ2.52(5H，m)。
Embodiment 3
With 3-{3-(3-(3-fluorophenyl)-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl }-the 1-picoline is a raw material, compound 20 synthetic with similar approach.
1H-NMR(CDCl
3，300MHz)：δ7.02-7.29(4H，m)，δ6.70(1H，m)，δ4.28(2H，s)，δ3.47(2H，d，J＝1.8)，δ2.63(2H，t，J＝5.1)，δ2.49(2H，m)，δ2.17(3H，s)。
Embodiment 4
The preparation of 3-(3-(3-phenyl-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl) pyridine (compound 15)
In the tetrahydrofuran solution of 0.2g (1.03mmol) 3-(3-sulfydryl-1,2,5-thiadiazoles-4-yl) pyridine, add 0.425g (3.08mmol) K
2CO
3Slowly splash into 0.216g (1.03mmol) 3-phenyl-2-propine methanesulfonates, ice bath stirred 7 hours, stirred overnight at room temperature.Stopped reaction adds 20ml water in reaction solution, with hydrochloric acid PH is transferred to 2, and the reaction solution concentrating under reduced pressure is used extracted with diethyl ether (30ml * 3) after removing tetrahydrofuran (THF), ether liquid anhydrous Na SO4 drying.Water layer transfers to 10-11 with 25% ammoniacal liquor with PH, uses extracted with diethyl ether (30ml * 3) again, ether liquid anhydrous Na SO
4Dry.Siccative in twice ether extraction liquid is leached, merge, be spin-dried for, be pale brown look oily matter.Column chromatography for separation obtains product 3-(3-(3-phenyl-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl) the yellowish powder of pyridine.
1H-NMR(CDCl
3，300MHz)：δ9.44(1H，s)，δ9.03(1H，d)，δ8.86(1H，d)，δ8.08(1H，t)，δ7.35-7.38(5H，m)，δ4.42(2H，s)。
Embodiment 5
With 3-(3-chloro-phenyl-)-2-propine methanesulfonates is raw material, and compound 18 usefulness similar approach are synthetic.
1H-NMR(CDCl
3，300MHz)：δ9.44(1H，s)，δ9.05(1H，d)，δ8.92(1H，d)，δ8.14(1H，t)，δ7.21-7.38(5H，m)，δ4.39(2H，s)
Embodiment 6
With 3-(3-fluorophenyl)-2-propine methanesulfonates is raw material, and compound 21 usefulness similar approach are synthetic.
1H-NMR(CDCl
3，300MHz)：δ9.19(1H，s)，δ8.72(1H，d)，δ8.35(1H，d)，δ7.55(1H，dd)，δ6.97-7.27(5H，m)，δ4.(2H，s)
Embodiment 7
The preparation of 3-(3-(3-phenyl-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl)-1-picoline (compound 16)
In the acetone soln of 12.81g (41mmol) 3-(3-(3-phenyl-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl) pyridine, add 7.75ml (124mmol) methyl iodide, a large amount of yellow mercury oxides appear in stirring at room one day in the reaction solution, filter, obtain yellow powder.
1H-NMR(DMSO，300MHz)：δ9.45(1H，s)，δ8.11(1H，d，J＝6)，δ8.97(1H，d，J＝8.1)，δ8.32(1H，dd，J1＝6，J2＝8.1)，δ7.35(5H，s)，δ4.48(2H，s)，δ4.44(3H，s).
Embodiment 8
With 3-{3-(3-(3-chloro-phenyl-)-2-propargyl-1-sulfenyl]-1,2,5-thiadiazoles-4-yl } pyridine is raw material, compound 19 synthetic with similar approach.
1H-NMR(DMSO，300MHz)：δ9.78(1H，s)，δ9.32(1H，s)，δ9.05(1H，d，J＝7.8)，δ8.29(1H，t，J＝3.9)，δ7.21-7.38(4H，m)，δ4.83(3H，s)，δ4.39(2H，s).
Embodiment 9
With 3-{3-(3-(3-fluorophenyl)-2-propargyl-1-sulfenyl)-1,2,5-thiadiazoles-4-yl } pyridine is raw material, compound 22 usefulness similar approach are synthetic.
1H-NMR(CDCl
3，300MHz)：δ9.69(1H，d，J＝6)，δ9.34(1H，s)，δ9.03(1H，d，J＝8.7)，δ8.32(1H，t，J＝6.6)，δ7.01-7.31(4H，m)，δ4.82(3H，s)，δ4.39(2H，s).
Claims (5)
1. the compound or its salt of following general formula (II):
Wherein Z is O or S; X is O or S; R is that 2～6 of phenyl ring are gone up single locational substituting group, and it is selected from: F, Cl, Br or I.
2. compound or its salt according to claim 1, wherein said salt are oxalate, hydrochloride or vitriol.
3. the preparation method of the compound shown in the following general formula (a),
Wherein this method is made up of following steps:
(1) be starting raw material with the 3-pyridylaldehyde, generate 3-(3-sulfydryl-1,2,5-thiadiazoles-4-yl) pyridine through following step, wherein 2-amino-2-(3-pyridyl) acetonitrile is synthetic through single step reaction:
(i)KCN，THF，NH
4Cl，NH
3(ii)S
2Cl
2，DMF(iii)NaSH，CH
3OH；
(2) the replacement iodobenzene with R is a raw material, generates the propine methanesulfonates of R substituted benzene through following step and propiolic alcohol condensation and with the Methanesulfonyl chloride esterification:
(i)(PPh
3)
2PdCl
2，CuI，Et
2NH(ii)CH
3SO
2Cl，CH
2Cl
2；
(3) product that obtains in step (1) and (2) is reacted the compound that generates general formula (b), methylate through methyl iodide, obtain the compound of general formula (a), wherein reactions steps is as follows:
(i) K
2CO
3, THF is CH (ii)
3I, acetone,
Wherein, R is selected from: F, Cl, Br or I.
4. compound or its salt according to claim 1 and 2 is used for exciting M in preparation
1Application in the medicine of acceptor.
5. application according to claim 4, wherein said medicine for the treatment Alzheimer's disease, strengthen learning and Memory function, improve cognitive function, short intelligence, medicine that neuroprotective is relevant.
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| EP4019018A1 (en) | 2015-09-11 | 2022-06-29 | Chase Pharmaceuticals Corporation | Muscarinic combination and its use for combating hypocholinergic disorders of the central nervous system |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045104A (en) * | 1989-02-22 | 1990-09-05 | 弗劳森公司 | Piperidine compounds and preparation thereof and purposes |
| WO1992003431A1 (en) * | 1990-08-21 | 1992-03-05 | Novo Nordisk A/S | Heterocyclic compounds and their preparation and use |
| US6015813A (en) * | 1997-04-22 | 2000-01-18 | Novo Nordisk A/S | Heterocyclic compounds and their preparation and use |
| US20020115697A1 (en) * | 1996-03-19 | 2002-08-22 | Lone Jeppesen | Heterocyclic compounds and their preparation and use |
-
2005
- 2005-08-30 CN CN 200510093492 patent/CN1821243B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045104A (en) * | 1989-02-22 | 1990-09-05 | 弗劳森公司 | Piperidine compounds and preparation thereof and purposes |
| WO1992003431A1 (en) * | 1990-08-21 | 1992-03-05 | Novo Nordisk A/S | Heterocyclic compounds and their preparation and use |
| US20020115697A1 (en) * | 1996-03-19 | 2002-08-22 | Lone Jeppesen | Heterocyclic compounds and their preparation and use |
| US6015813A (en) * | 1997-04-22 | 2000-01-18 | Novo Nordisk A/S | Heterocyclic compounds and their preparation and use |
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| Title |
|---|
| Lone Jeppesen, et al,.1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0] heptanesasnewpotent muscarinic M1 agonists:Structure-activityrelationshipfor 3-aryl-2-propyn-1-yloxyand3-Aryl-2-propyn-1-ylthioderivatives,.J. Med. Chem.,42, 11.1999,42,(11),1999-2006. |
| Lone Jeppesen, et al,.1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0] heptanesasnewpotent muscarinic M1 agonists:Structure-activityrelationshipfor 3-aryl-2-propyn-1-yloxyand3-Aryl-2-propyn-1-ylthioderivatives,.J. Med. Chem.,42, 11.1999,42,(11),1999-2006. * |
| Medicinal Chemistry Letters,8.1998,82897-2902. * |
| Per Sauerberg, et al,.Identification of side chains on1,2,5-thiadaizole-azacyclesoptimal for muscarinic M1 receptoractivation.Bioorgnic & Medicinal Chemistry Letters,8.1998,82897-2902. |
| Per Sauerberg, et al,.Identification of side chains on1,2,5-thiadaizole-azacyclesoptimal for muscarinic M1 receptoractivation.Bioorgnic & * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4019018A1 (en) | 2015-09-11 | 2022-06-29 | Chase Pharmaceuticals Corporation | Muscarinic combination and its use for combating hypocholinergic disorders of the central nervous system |
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