CN106008494B - One kind -2- thioxothiazole alkyl derivative of oxo containing 4- and the preparation method and application thereof - Google Patents
One kind -2- thioxothiazole alkyl derivative of oxo containing 4- and the preparation method and application thereof Download PDFInfo
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
The invention discloses a kind of -2- thioxothiazole alkyl derivatives of oxo containing 4- and the preparation method and application thereof, belong to biomedicine technical field.Derivative of the present invention includes compound of Formula I, and wherein n is integer 1 or 2；R1For ester group or amide or acidic group；R2For one of hydrogen, isopropyl or methoxyl group.Such majority of compounds is not only inhibited to Protein tau polymerization, but also plays stabilization to tubulin, can be effectively used for treatment azheimer's disease.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of -2- thioxothiazole alkyl derivative of oxo containing 4-
And the preparation method and application thereof.
Background technique
Alzheimer's disease (Alzheimer ' s disease, AD) is chronic progressive central nervous system degeneration
Caused dementia is the dull-witted most common cause of disease and the most common senile dementia.AD is with gradual memory obstacle, cognitive function
The neuropsychic symptoms such as obstacle, personality change and aphasis are characterized.Normal onset is in old or presenium, more slowly hairs
Disease is gradually in progress, and is main performance with dementia.The cause of disease is unknown so far, there is no the specific medicament or method of healing at present.However suffer from
Person's number but increases in the whole world year by year, existing 5,000,000 people of patient of China, will be up to 10,000,000 people to the year two thousand twenty.To the year two thousand fifty, the whole world
Alzheimer's disease patient will be significantly increased, and be horizontal at present 4 times, this number will increase to 1.06 hundred million, and Asia will be
Severely afflicated area accounts for nearly the 60% of whole degenerative brain disorder patients.With the extension of human longevity and the world aging epoch
It arrives, " time bomb " of this publilc health will be detonated, thus cause the common concern of people.
More and more researches show that occurring first 10~20 years early in AD symptom, the pathological change in brain is had occurred and that.
Mainly there are 3 kinds of hypothesis: amyloid beta deposition, neurofibrillary tangles at present for the pathomechanism of AD
(neurofibrillary tangles, NFTs) and cholinergic neuron retrogression pathological changes.In more than ten years in past, anti-AD medicine
The research of object mostly concentrates on the relevant strategy of A β cascade hypothesis, but recently, faces using A β as some drugs of target spot in three phases
Bed test in but end in failure, thus " neurofibrillary tangles " AD disease in effect be widely recognized as by people.
Tau albumen is a kind of low molecular weight being distributed in central nervous system containing phosphoglucoprotein, it can and neural axon
Interior micro-pipe combines, and there is induction to prevent microtubule depolymerization at micro-pipe with tubulin polymerization is promoted, maintain the steady of micro-pipe function
It is fixed, it plays an important role to memory and Normal brain function.Tau protein hyperphosphorylation causes Tau albumen occurred conformation to change,
It is easy to be gathered into double helix fiber (PHF), and then precipitates and form neurofibrillary tangles, under pathological state, free Tau egg
White continuous peroxophosphoric acid makes the combination of itself and tubulin there was only the 10% of normal Tau albumen, and has fettered Tau albumen to micro-
The stabilization of pipe causes degeneration of nerve fibers and function to lose, forms NFTs.NFTs itself is harmless to cell, but Tau protein delation
The dynamic behaviour of micro-pipe can be made by strong influence, micro-pipe tends to dissociate due to losing the stabilization of Tau albumen, causes thin
The collapse of born of the same parents' skeleton influences the transmitting or even cell death of axonal transport function and nerve signal.Tau protein hyperphosphorylation
Not only make itself to promote microtubules activity to reduce, at the same also by consume normal Tau albumen, microtubule associated protein MAP1 and
MAP2 further destroys micro-pipe, influences synthesis, transport, release and the intake of neurotransmitter, and the communication between nerve cell is caused to hinder
Hinder, so as to cause nervus retrogression.In addition, many researchs have confirmed, the abnormal modification of Tau causes Tau to become toxicity molecule
And build up into PHF, so that neurofibrillary degeneration occur.Therefore, in recent years, Protein tau is as Alzheimer's disease target spot
The research of drug receives more and more attention.
It is still in primary stage, most medicines at present by the research of target treatment Alzheimer's disease of Protein tau
Object small molecule is also in the Theoretical Design stage, and only sub-fraction enters phase ii clinical trial, integrates present Research both domestic and external,
Protein tau inhibitor mainly develops towards both direction at present: (1) research of the research of indirect inhibitor, such drug mainly collects
In in the research to Protein tau phosphorylation relevant enzyme.The research of direct inhibitor, the molecule of such drug is directly and Protein tau
It interacts and inhibits its aggregation.Such as methyl blue (MTC), this phenothiazine compound can prevent between tau-tau
Interaction, it can not only partly decompose isolated double helix fiber filament (PHFs), moreover it is possible to influence the polymerization of Protein tau
Journey.The research of current this kind of drug has entered the second stage of clinical stage.
In addition, based on to pathomechanism relevant to Protein tau in AD pathogenic process, it being capable of generation using the stabilizer of micro-pipe
The missing for repaying Protein tau function adjusts the dynamic stability of micro-pipe, it is made to restore the function of normal mediating axonal transport, because
And it protects nerve cell and achievees the purpose that treat azheimer's disease.By protecting primary neural cell to lure from A β with taxol
The neurotoxicity led, improve Neuronal Survival rate research in find, in neuronal cell cultures liquid be added toxicity peptide fragment it
Afterwards, the Neuronal Survival rate crossed with taxol treatment is apparently higher than untreated nerve cell, dies relevant albumen moreover, adjusting
The activity of enzyme caspase3 is substantially reduced, and is shown that taxol can slow down the pathogenesis of neurofibrillary tangles, is made up tau egg
It is white to lack the reduction for causing microtubule stability, and then guarantee the integrality of neuron.In subsequent research, and find taxol
The multiple proteins such as some bearing taxanes (Taxanes) and Epothilones (epothilone) in addition missing causes micro-pipe
Stabilizer all significantly improves Neuronal Survival rate in the presence of A β, while cell being helped to keep the complete of cytoskeleton network
Property, makes it avoid the damage of the toxicity cascade reaction as caused by β sections of A, they are to the therapeutic effect of AD in zoopery
It is confirmed.
Summary of the invention
According to above-mentioned AD pathomechanism, the purpose of the present invention is to provide one kind -2- thioxothiazole alkyl of oxo containing 4- to spread out
The biology, -2- of oxo containing the 4- thioxothiazole alkyl derivative are small point for capable of acting on Protein tau and the double target spots of tubulin
Son not only polymerize inhibited but also plays stabilization to tubulin, for treating Alzheimer's disease to Protein tau.
It is another object of the present invention to provide the preparations with the above-mentioned -2- of oxo containing 4- thioxothiazole alkyl derivative
Method.
Another object of the present invention is to provide the applications of the above-mentioned -2- of oxo containing 4- thioxothiazole alkyl derivative.Using
In the drug of preparation treatment azheimer's disease.
The purpose of the invention is achieved by the following technical solution: a kind of -2- thioxothiazole alkyl derivative of oxo containing 4-, institute
The structural formula of derivative is stated as shown in following formula I:
Wherein: n is integer 1 or 2；
R1For ester group or amide or acidic group；
R2For one of hydrogen, isopropyl or methoxyl group；
The preparation method of above-mentioned compound of formula I includes the following steps: 2- carboxylic acid benzo acid anhydrides directly and anil
Reaction, tetrahydrofuran borane reduction reaction, wear this Martin and be oxidized to aldehyde reaction, Knoevenagel condensation reaction and de- ester are anti-
The derivative of -2- thioxothiazole the alkyl of oxo containing 4- should be generated, solvent for use is tetrahydrofuran or methylene chloride.
The specific preparation method of above-mentioned type I compound, the specifically preparation of the method as described in step (1) and step (2) obtain
:
(1) preparation of 2- (4- oxo -2- Thioxothiazolidin -3- base) acetic acid or propionate intermediate 1: from the sweet ammonia of commercialization
Acetoacetic ester, t-butyl ester hydrochloride or 3- alanine ethyl ester, t-butyl ester hydrochloride set out, using triethylamine as alkali, with 2,2'-
Condensation reaction occurs for (thiocarbonyl (sulphur)) diacetin hydrochlorate, is purified later by column chromatography, white solid can be obtained
Compound 1, the condensation reaction select isopropanol as reaction dissolvent, and flow back 1h at 82 DEG C, and the reaction equation of step (1) is such as
Shown in formula II；
(2) 6 preparation: since compound 5 first 2- carboxylic acid benzo acid anhydrides is commercialized, be not added any solvent and urging
Directly in heating temperature to being kept for 2 hours at 200 DEG C in the case where the agent of change, after crossing column purification, available compound 2；It
Afterwards, with tetrahydrofuran borane reduction compound 2, reaction dissolvent uses methylene chloride or tetrahydrofuran, and reaction carries out 12 hours, adds
Enter spirit of vinegar, make its pH value 3-4, obtains alcohol compound 3 through column chromatography；Then compound 3 is dissolved in methylene chloride,
Addition wears this Martin's oxidant and hydroxyl is further oxidized to aldehyde, reacts substantially 1 hour, obtains aldehydes with column chromatography
Close object 4；Compound 4 is dissolved in methylene chloride, intermediate 1 is added and carries out Knoevenagel condensation reaction, 1 is small at normal temperature
Shi Hou is purified by column chromatography, obtains compound 5；Later, under trifluoroacetic acid acid condition, compound 5 (5a1,5a2,
5b2,5b2) degreasing reaction is carried out, acid compound 6 is formed, is in yellow solid after recrystallization；Compound 5,6 is Formulas I chemical combination
Object, the reaction equation of step (2) is as shown in formula III；
The application of the above-mentioned -2- thioxothiazole alkyl derivative of oxo containing 4-, applied to preparation treatment azheimer's disease
Drug.
The present invention has the following advantages and effects with respect to the prior art:
Not only Protein tau self aggregation has preferable inhibit to -2- the thioxothiazole of oxo containing 4- alkyl derivative of the invention
Activity, and there is very strong stabilization to tubulin polymerization.Thus, by the former effect, neuron can be prevented
The formation of fibre matting to prevent tubulin depolymerization, then by the effect of the latter, further adjusts the dynamic stability of micro-pipe
Property, so that it is restored the function of normal mediating axonal transport, thus protect nerve cell and reach the mesh for treating azheimer's disease
's.
Detailed description of the invention
Fig. 1 is that compound 5 is serial to the result figure for increasing tubulin polymerization rate in table 1.
Fig. 2 is that compound 6 is serial to the result figure for increasing tubulin polymerization rate in table 1.
Specific embodiment
Present invention will now be described in further detail with reference to the embodiments and the accompanying drawings, but embodiments of the present invention are unlimited
In this.
Embodiment 1
Synthesize 2- (4- oxo -2- Thioxothiazolidin -3- base) ethyl acetate 1a1
Glycine ethyl ester hydrochloride (500mg, 3.6mmol, 1eq) is added to dissolved with 2,2'- (thiocarbonyl (sulphur)) two
In the isopropanol (4mL) of acetic acid (976mg, 4.32mmol, 1.2eq), Et is then instilled into system again3N(1mL,7.2mmol,
2eq).Reaction system is heated to 82 ° degrees Celsius, stirs 1h.TLC is monitored after reaction, after concentration is dry, through silica gel post separation
It obtains product 1a1 (638mg, 2.91mmol), yellow crystalline solid, fusing point: 55 DEG C, yield 81%.
1H NMR(400MHz,CDCl3) δ=4.65 (s, 2H), 4.19 (q, J=7.8Hz, 2H), 4.01 (s, 2H), 1.22
(t, J=7.8Hz, 3H)；ESI-MS m/z:220.2[M+H]+。
Embodiment 2
Synthesize 2- (4- oxo -2- Thioxothiazolidin -3- base) tert-butyl acetate 1a2
Glycine tert-butyl hydrochloride (500mg, 3mmol, 1eq) and trithiocarbonate (813mg, 3.6mmol,
1.2eq) referring to 1 operating process of embodiment, compound 1a2 (504mg) is separated to obtain, yellow crystalline solid, fusing point: 56 DEG C, yield
68%.
1H NMR(400MHz,CDCl3) δ=4.62 (s, 2H), 4.07 (s, 2H), 1.46 (s, 9H)；ESI-MS m/z:
248.2[M+H]+。
Embodiment 3
Synthesize 2- (4- oxo -2- Thioxothiazolidin -3- base) ethyl propionate 1b1
3- alanine carbethoxy hydrochloride (500mg, 3.27mmol, 1eq) and 2,2'- (thiocarbonyl (sulphur)) oxalic acid
(886mg, 3.92mmol, 1.2eq) separates to obtain product 1b1 (708mg) referring to 1 operating process of embodiment, yellow crystalline solid,
Fusing point: 53 DEG C, yield 93%.
1H NMR(400MHz,CDCl3) δ 4.30 (t, J=7.8Hz, 2H), 4.18 (q, J=7.8Hz, 2H), 4.00 (s,
2H), 2.68 (t, J=7.8Hz, 2H), 1.27 (t, J=7.7Hz, 3H)；ESI-MS m/z:234.1[M+H]+。
Embodiment 4
Synthesize 2- (4- oxo -2- Thioxothiazolidin -3- base) propanoic acid tert-butyl ester 1b2
3- alanine t-butyl ester hydrochloride (500mg, 2.76mmol, 1eq) and 2,2'- (thiocarbonyl (sulphur)) oxalic acid
(749mg, 3.15mmol, 1.2eq) separates to obtain product 1b2 (467mg) referring to 1 operating process of embodiment, yellow crystalline solid,
Fusing point: 52 DEG C, yield 62%.
1H NMR(400MHz,CDCl3) δ 4.25 (t, J=7.8Hz, 2H), 3.98 (s, 2H), 2.61 (t, J=7.8Hz,
2H),1.45(s,9H)；ESI-MS m/z:262.1[M+H]+。
Embodiment 5
Synthesize 2- (2,6- diisopropyl phenyl) -1,3- dioxo isoindoline -5- formaldehyde 4a
2- carboxylic acid benzo acid anhydrides (100mg, 0.49mmol, 1eq) and 2,6 diisopropyl anilines (4.9mmol, 10eq) are abundant
Mixing, stirring, is heated to 200 DEG C or so for reaction temperature, it can be observed that reaction solution color obviously deepens.It is anti-with TLC monitoring
After should being completely disappeared to raw material, after the Methods For Purification with column chromatography, then recrystallizes, obtain product 2a, white solid, fusing point: 234
DEG C, yield 83%.
1H NMR(400MHz,CDCl3) δ 8.71 (d, J=2.4Hz, 1H), 8.60 (dd, J=7.8,2.4Hz, 1H), 8.11
(d, J=7.8Hz, 1H), 7.49 (t, J=7.8Hz, 1H), 7.32 (d, J=7.8Hz, 1H), 2.69 (hept, J=7.8Hz,
2H), 1.19 (d, J=7.8Hz, 12H)
Compound 2a (500mg, 1.42mmol, 1eq) is dissolved completely in tetrahydrofuran (10mL), then in ice bath
Under the conditions of tetrahydrofuran-borine (4.27mmol, 1mol/L, 3eq) is added dropwise, stir 12h, reaction solution face at normal temperature later
Color obviously deepens, and after being completely disappeared with TLC monitoring reaction to raw material, reaction solution is spin-dried for, then be dissolved in (3M, 50mL) acetic acid
It in solution, is extracted later with ethyl acetate (50mL x 2), collects extract liquor, the Methods For Purification chromatographed after being spin-dried for column obtains
Compound 3a, white solid, fusing point: 136 DEG C, yield 68%.
1H NMR(400MHz,CDCl3) δ 7.99 (dd, J=7.8,2.4Hz, 1H), 7.95 (dd, J=7.8,2.4Hz,
1H), 7.81 (d, J=7.8Hz, 1H), 7.46 (t, J=7.8Hz, 1H), 7.30 (d, J=7.8Hz, 2H), 4.90 (s, 2H),
2.7 (hept, J=7.8Hz, 2H), 1.17 (d, J=7.8Hz, 12H)
Compound 3a (0.58mmol, 1eq) is completely dissolved in methylene chloride (5mL), is then slowly added into and wears this Martin
Oxidant (500mg, 1.17mmol, 2eq) stirs under conditions of room temperature.It can be observed that reaction solution color is deepened, 2h is reacted,
With TLC monitoring reaction completely disappeared to raw material after, after reaction solution is spin-dried for, be added containing sodium bicarbonate aqueous solution (5M,
50mL), it is then extracted with ethyl acetate (50mL x 2).The Methods For Purification that combining extraction liquid is chromatographed after being spin-dried for column, is changed
Conjunction object 4a, white solid, fusing point: 153 DEG C, yield 90%.
1H NMR (400MHz, Acetone) δ 10.31 (s, 1H), 8.50 (dd, J=2.4Hz, 1H), 8.47 (dd, J=
7.8,2.4Hz, 1H), 8.22 (d, J=7.8Hz, 1H), 7.51 (t, J=7.8Hz, 1H), 7.38 (d, J=7.8Hz, 2H),
2.87 (hept, J=7.8Hz, 2H), 1.15 (d, J=7.8Hz, 12H)
Embodiment 6
Synthesize 1,3- dioxy -2- (3,4,5- trimethoxyphenyl) iso-indoles -5- formaldehyde 4b
From commercialization 2- carboxylic acid benzo acid anhydrides (0.49mmol) and 3,4,5- trimethoxy-anilines (4.82mmol) are joined from hair
According to 5 operating process of embodiment, compound 4b is separated to obtain, yellow solid, fusing point: 184 DEG C, total recovery 44%.
Compound 2b:1H NMR (400MHz, DMSO) δ 8.48 (d, J=2.4Hz, 1H), 8.36 (dd, J=7.6Hz,
1H), 8.13 (d, J=7.6Hz, 1H), 6.88 (s, 2H), 3.82 (s, 6H), 3.78 (s, 3H)
Compound 3b:1H NMR (400MHz, DMSO) δ 7.91 (d, J=2.4Hz, 1H), 7.87 (dd, J=7.6Hz,
1H), 7.82 (d, J=7.7Hz, 1H), 6.80 (s, 2H), 4.71 (s, 2H), 3.77 (s, 6H), 3.72 (s, 3H)
Compound 4b:1H NMR (400MHz, DMSO) δ 10.23 (s, 1H), 8.40 (d, J=2.3Hz, 1H), 8.39 (dd,
J=7.6Hz, 1H), 8.16 (d, J=7.6Hz, 1H), 6.83 (s, 2H), 3.77 (s, 6H), 3.73 (s, 3H)
Embodiment 7
Synthesize (E)-2- (5-((1,3- dioxo-2- (2,6- isopropyl) iso-indoles-5- base) methylene)-4- oxo-2-
Thio thiophane -3- base) ethyl acetate 5a1
Compound 4a (33mg, 0.1mmol, 1eq) and 1a1 (21mg, 0.1mmol, 1eq) is filled with methylene chloride (1mL)
It after dividing dissolution, is slowly added dropwise piperidines (20 μ L), keeps under normal temperature conditions, it can be observed that reaction solution obviously reddens, reaction
30min.With TLC monitoring reaction completely disappeared to raw material after, after reaction solution is spin-dried for, be added containing glacial acetic acid aqueous solution (5M,
10mL), it is then extracted with ethyl acetate (10mL x 2).The Methods For Purification that combining extraction liquid is chromatographed after being spin-dried for column, is changed
Conjunction object 5a1, yellow solid, fusing point: 210 DEG C, yield 46%.
1H NMR(400MHz,CDCl3) δ 8.08 (d, J=2.4Hz, 1H), 8.02 (dd, J=7.8,2.4Hz, 1H), 7.91
(d, J=7.8Hz, 1H), 7.86 (s, 1H), 7.48 (t, J=7.8Hz, 1H), 7.32 (s, 1H), 7.30 (d, J=7.8Hz,
1H), 4.89 (s, 2H), 4.27 (q, J=7.8Hz, 2H), 2.69 (hept, J=7.8Hz, 2H), 1.31 (t, J=7.1Hz,
3H), 1.17 (d, J=7.8Hz, 12H)；ESI-MS m/z:537.2[M+H]+。
Embodiment 8
Synthesize (E)-2- (5-((1,3- dioxo-2- (2,6- isopropyl) iso-indoles-5- base) methylene)-4- oxo-2-
Thio thiophane -3- base) tert-butyl acetate 5a2
From compound 4a (0.1mmol) and 1a2, (the 0.1mmol) separates to obtain chemical combination referring to 7 operating process of embodiment
Object 5a2, yellow solid, fusing point: 125 DEG C, yield 65%；
1H NMR(400MHz,CDCl3) δ 8.08 (d, J=2.4Hz, 1H), 8.06 (dd, J=7.8,2.4Hz, 1H), 7.91
(d, J=7.8Hz, 1H), 7.85 (s, 1H), 7.48 (t, J=7.8Hz, 1H), 7.32 (d, J=7.8Hz, 2H), 4.79 (s,
2H), 2.69 (hept, J=7.8Hz, 2H), 1.49 (s, 9H), 1.17 (d, J=7.8Hz, 12H)；ESI-MS m/z:565.2[M
+H]+。
Embodiment 9
Synthesize (E) -3- (5- ((2- (2,6- diisopropyl phenyl) -1,3- dioxo isoindoline -5- base) methylene
Base) -4- oxo -2- Thioxothiazolidin -3- base) ethyl propionate 5a3
From compound 4a (0.1mmol) and 1b1, (the 0.1mmol) separates to obtain chemical combination referring to 7 operating process of embodiment
Object 5a3, yellow solid, fusing point: 118 DEG C, yield 48%.
1H NMR(400MHz,CDCl3) δ 8.07 (d, J=2.4Hz, 1H), 8.05 (dd, J=7.8,2.4Hz, 1H), 7.90
(d, J=7.8Hz, 1H), 7.82 (s, 1H), 7.48 (t, J=7.8Hz, 1H), 7.32 (d, J=7.8Hz, 2H), 4.46 (t, J=
7.8Hz, 2H), 4.17 (a, J=7.8Hz, 2H), 2.79 (t, J=7.8Hz, 2H), 2.68 (hept, J=7.8Hz, 2H), 1.28
(t, J=7.8Hz, 3H), 1.17 (d, J=7.8Hz, 12H)；ESI-MS m/z:551.2[M+H]+。
Embodiment 10
Synthesize (E) -3- (5- ((2- (2,6- diisopropyl phenyl) -1,3- dioxo isoindoline -5- base) methylene
Base) -4- oxo -2- Thioxothiazolidin -3- base) propanoate 5a4
From compound 4a (0.1mmol) and 1b2, (the 0.1mmol) separates to obtain chemical combination referring to 7 operating process of embodiment
Object 5a4, yellow solid, fusing point: 141 DEG C, yield 68%.
1H NMR(400MHz,CDCl3) δ 8.07 (d, J=7.9Hz, 1H), 8.05 (dd, J=7.9,2.4Hz, 1H), 7.91
(d, J=7.9Hz, 1H), 7.82 (s, 1H), 7.47 (t, J=7.9Hz, 1H), 7.32 (d, J=7.9Hz, 2H), 4.42 (t, J=
7.9Hz, 2H), 2.70 (hept, J=7.9Hz, 2H), 2.73 (t, J=7.9Hz, 2H), 1.45 (s, 9H), 1.16 (d, J=
7.9Hz,12H)；ESI-MS m/z:579.2[M+H]+。
Embodiment 11
Synthesize (E)-2- (5-((1,3- dioxo-2- (3,4,5- trimethoxyphenyl) isoindoline-5- base) methylenes
Base) -4- oxo 2- Thioxothiazolidin -3- base) ra-butyl acetate 5b2
From compound 4b (0.1mmol) and 1a2, (the 0.1mmol) separates to obtain chemical combination referring to 7 operating process of embodiment
Object 5b2, yellow solid, fusing point: 155 DEG C, yield 39%.
1H NMR(400MHz,CDCl3) δ 8.06 (d, J=2.4Hz, 1H), 8.04 (dd, J=7.8,2.4Hz, 1H), 7.90
(d, J=7.8Hz, 1H), 7.85 (s, 1H), 6.65 (s, 2H), 4.79 (s, 2H), 3.90 (s, 3H), 3.89 (s, 6H), 1.48
(s,9H)；ESI-MS m/z:571.1[M+H]+。
Embodiment 12
Synthesize (E)-3- (5-((1,3- dioxo-2- (3,4,5- trimethoxyphenyl) iso-indoles-5- base) methylene)-
4- oxo -2- Thioxothiazolidin -3- base) propanoate 5b4
From compound 4b (0.1mmol) and 1b2, (the 0.1mmol) separates to obtain chemical combination referring to 7 operating process of embodiment
Object 5b4, yellow solid, fusing point: 165 DEG C, yield 38%.
1H NMR(400MHz,CDCl3) δ 8.05 (d, J=2.4Hz, 1H), 8.03 (dd, J=7.8,2.4Hz, 1H), 7.88
(d, J=7.8Hz, 1H), 7.81 (s, 1H), 6.65 (s, 2H), 4.42 (t, J=7.8Hz, 2H), 3.90 (s, 3H), 3.88 (s,
6H), 2.70 (t, J=7.8Hz, 2H), 1.45 (s, 9H)；ESI-MS m/z:585.1[M+H]+。
Embodiment 13
Synthesize (E) -2- (5- ((2- (2,6- diisopropyl phenyl) -1,3- dioxo isoindoline -5- base) methyl) -
4- oxo -2- Thioxothiazolidin -3- base) acetic acid 6a1
From compound 5a2, (trifluoro second is added after methylene chloride (0.5mL) dissolution in the 0.044mmol) at normal temperature
Sour (0.5mL) the temperature remains within the normal range lower 2h.It can be observed that there is a small amount of precipitating to generate.After being completely disappeared with TLC monitoring reaction to raw material,
Then anhydrous ether (10mL) is instilled in reaction solution can observe a large amount of yellow solids appearance, and compound 6a1 is obtained by filtration,
Yellow solid, fusing point: 123 DEG C, yield 81%.
1H NMR(400MHz,(CD3)2CO) δ 8.24 (d, J=2.4Hz, 1H), 8.21 (dd, J=7.8,2.4Hz, 1H),
8.18 (d, J=7.8Hz, 1H), 8.07 (s, 1H), 7.51 (t, J=7.8Hz, 1H), 7.38 (d, J=7.8Hz, 2H), 4.93
(s, 2H), 2.82 (hept, J=7.8Hz, 2H), 1.15 (d, J=7.8Hz, 12H)；ESI-MS m/z:509.1[M+H]+。
Embodiment 14
Synthesize (E)-3- (5-((2- (2,6- diisopropyl phenyl)-1,3- dioxo isoindoline-5- base) methylenes
Base) -4- oxo -2- Thioxothiazolidin -3- base) propionic acid 6a2
From compound 5a4 (the 0.044mmol) obtains compound 6a2 referring to 13 operating process of embodiment after filtering,
Yellow solid, fusing point: 142 DEG C, yield 89%.
1H NMR(400MHz,(CD3)2CO) δ 8.20 (m, 3H), 7.99 (s, 1H), 7.51 (t, J=7.8Hz, 1H), 7.38
(d, J=7.8Hz, 2H), 4.43 (t, J=7.8Hz, 2H), 2.86 (m, 4H), 1.15 (d, J=7.8Hz, 12H)；ESI-MS m/
z:523.1[M+H]+。
Embodiment 15
Synthesize (E)-2- (5-((1,3- dioxo-2- (3,4,5- trimethoxyphenyl) isoindoline-5- base) methylenes
Base) -4- oxo 2- Thioxothiazolidin -3- base) acetic acid 6b1
From compound 5b2 (the 0.044mmol) obtains compound 6b1 referring to 13 operating process of embodiment after filtering,
Yellow solid, fusing point: 160 DEG C, yield 92%.
1H NMR(400MHz,(CD3)2CO)δ8.23–8.15(m,4H),6.85(s,2H),4.93(s,2H),3.84(s,
6H),3.79(s,3H)；ESI-MS m/z:515.1[M+H]+。
Embodiment 16
Synthesize (E)-3- (5-((1,3- dioxo-2- (3,4,5- trimethoxyphenyl) iso-indoles-5- base) methylene)-
4- oxo -2- Thioxothiazolidin -3- base) propionic acid 6b2
From compound 5b4 (the 0.044mmol) obtains compound 6b2 referring to 13 operating process of embodiment after filtering,
Yellow solid, fusing point: 192 DEG C, yield 87%.
1H NMR (400MHz, DMSO) δ 12.55 (s, 1H), 8.18 (d, J=2.4Hz, 1H), 8.09 (m, 3H), 6.83
(s, 2H), 4.26 (t, J=7.5Hz, 2H), 3.77 (s, 6H), 3.73 (s, 3H), 2.67 (t, J=7.5Hz, 2H)；ESI-MS
m/z:529.1[M+H]+。
Ira vitro tube albumen polymerization inhibiting activity test method:
Tubulin polymerization is to be detected by nephelometry in 384 orifice plates.4 DEG C and buffer (80mM PIPES,
pH 7.0,1mM EGTA,1mM MgCl2) in, tubulin (4mg/mL) and various compounds (1 μM) preculture 30min, it
Afterwards, 1mM GTP is added, test sample is rapidly heated to 37 DEG C.Then thermostatic control spectrophotometer (Spectramax is used
Paradigm, Molecular Devices, San Francisco, CA, USA), suction of the periodic measurement per minute at 340nm
Light varience.In test, taxol and nocodazole are used as stabilizer and disrupting agent control.
Thioflavin-S (ThS) test method of external Tau albumen polymerization inhibiting activity:
At 37 DEG C, in 384 orifice plates, Tau albumen (5 μM) and heparin (2.5 μM), ammonium acetate (50mM) and various chemical combination
Object (5 μM) is cultivated 24 hours simultaneously.Later, it is 20 μM that thioflavin-S, which is added, and arrives ultimate density.It is surveyed using sepectrophotofluorometer
Fixed (Spectramax Paradigm, Molecular Devices, San Francisco, CA, USA) fluorescent value.Launch wavelength
In 440nm excitation wavelength in 520nm.
It is listed as follows according to the Activity Results that the above method tests gained part of compounds:
Table 1:Tau albumen self aggregation inhibiting rate and tubulin polymerization increment rate
From table 1 and Fig. 1-2 as it can be seen that except 6b2 is a bit weaker, compound is greatly divided all to compare except part of compound 6b1
Taxol has the ability of stronger stable tubulin polymerization.Especially compound 5a4 has tubulin polymerization preferable
Stabilization, while there is a degree of inhibitory activity to tau self aggregation, it is expected to become the anti-azheimer's disease drug of multiple target point
Lead compound.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (4)
1. a kind of -2- thioxothiazole alkyl derivative of oxo containing 4-, it is characterised in that: the structural formula of the derivative such as following formula I
It is shown:
Wherein: n, R1、R2It is as follows:
2. the preparation method of -2- of oxo containing 4- thioxothiazole alkyl derivative described in claim 1, it is characterised in that: including
Following steps: 2- carboxylic acid benzo acid anhydrides is directly reacted with anil, this Martin oxidation is worn in the reaction of tetrahydrofuran borane reduction
At aldehyde reaction, the derivative of Knoevenagel condensation reaction and the de-ester reaction generation -2- of oxo containing 4- thioxothiazole alkyl, institute
It is tetrahydrofuran or methylene chloride with solvent.
3. the preparation method of -2- of oxo containing 4- thioxothiazole alkyl derivative described in claim 1, it is characterised in that: specific
The method as described in step (1) and step (2) prepares:
(1) preparation of 2- (4- oxo -2- Thioxothiazolidin -3- base) acetic acid or propionate intermediate 1: from commercialization glycine second
Ester hydrochloride, glycine tert-butyl hydrochloride, 3- alanine carbethoxy hydrochloride or 3- alanine t-butyl ester hydrochloride set out,
Using triethylamine as alkali, condensation reaction occurs with 2,2'- (thiocarbonyl (sulphur)) oxalic acid, is purified later by column chromatography,
Compound as white solid 1 can be obtained, which selects isopropanol as reaction dissolvent, and flow back 1h at 82 DEG C；
(2) compound 5,6 preparation: first will be commercialized 2- carboxylic acid benzo acid anhydrides and 2,6 diisopropyl anilines or 3,4,5- tri-
Aminoanisole mixing, it is directly small to holding 2 at 200 DEG C in heating temperature in the case where any solvent and catalyst is not added
When, after crossing column purification, available compound 2；Later, with tetrahydrofuran borane reduction compound 2, reaction dissolvent is using dichloro
Methane or tetrahydrofuran, reaction carry out 12 hours, and spirit of vinegar is added, makes its pH value 3-4, obtains alcohols chemical combination through column chromatography
Object 3；Then compound 3 is dissolved in methylene chloride, addition wears this Martin's oxidant and hydroxyl is further oxidized to aldehyde, and reaction is big
1 hour is caused, obtains aldehyde compound 4 with column chromatography；Compound 4 is dissolved in methylene chloride, intermediate 1 is added and carries out
Knoevenagel condensation reaction is purified at normal temperature after 1 hour by column chromatography, and compound 5 is obtained；Later, in trifluoro
Under the conditions of acetic acid, compound 5 carries out degreasing reaction, forms acid compound 6, is in yellow solid after recrystallization；Compound
5,6 be the -2- of oxo containing 4- thioxothiazole alkyl derivative.
4. the application of -2- of oxo containing 4- thioxothiazole alkyl derivative described in claim 1, it is characterised in that: be applied to system
The drug of standby treatment Alzheimer's disease.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1091006A (en) * | 1992-09-10 | 1994-08-24 | 伊莱利利公司 | Chemical compound as blood sugar lowering and treatment degenerative brain disorder |
| WO2013183718A1 (en) * | 2012-06-06 | 2013-12-12 | 国立大学法人京都大学 | Screening method, protein instability and/or stability inducers, and protein activity assesment |
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2016
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1091006A (en) * | 1992-09-10 | 1994-08-24 | 伊莱利利公司 | Chemical compound as blood sugar lowering and treatment degenerative brain disorder |
| WO2013183718A1 (en) * | 2012-06-06 | 2013-12-12 | 国立大学法人京都大学 | Screening method, protein instability and/or stability inducers, and protein activity assesment |
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| Title |
|---|
| Rhodanine and Thiohydantion Derivatives for Detecting Tau Pathology in Alzheimer"s Brains;Masahiro Ono et al.;《ACS Chem. Neurosci》;20110321;第2卷;第269-275页 * |
| Rhodanine-Based Tau Aggregation Inhibitors in Cell Models of Tauopathy;Bruno Bulic et al.;《Angew. Chem. Int. Ed》;20071105;第46卷;第9215-9219页 * |
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