CN101914031B - Pregabalin derivative and application thereof - Google Patents
Pregabalin derivative and application thereof Download PDFInfo
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- CN101914031B CN101914031B CN 201010242645 CN201010242645A CN101914031B CN 101914031 B CN101914031 B CN 101914031B CN 201010242645 CN201010242645 CN 201010242645 CN 201010242645 A CN201010242645 A CN 201010242645A CN 101914031 B CN101914031 B CN 101914031B
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- lyrica
- ester hydrochloride
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Abstract
The invention relates to a pregabalin derivative shown in formula I and application thereof in medicine for resisting senile dementia. Acetylcholinesterase in vitro test model shows that the pregabalin derivative has remarkable acetylcholinesterase resistance activity so as to be used for preparing the medicine for resisting senile dementia. The pregabalin derivative has the chemical structural formula shown by the formula I, and R in the formula is defined by the specification. Formula I.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, particularly, the present invention relates to new pregabalin derivative and application thereof.
Technical background
Along with the aging of whole world population, (be commonly called as senile dementia, Alzhemer ' s disease AD) becomes and threatens one of principal disease that the old man lives old age alzheimer's disease.AD is a kind of carrying out property of irreversible brain regression disease.Clinical manifestation is the acquired hypophrenia that hypomnesis damages with other recognizing abilities, causes patients with terminal to lose the ability of information such as comprehensively looking, listen, touch, smell, causes the patient not live on one's own life.The pathogenesis complexity of AD, nosetiology are unclear fully as yet, do not have the medicine of good radical cure or the reverse course of disease so far.At present, the cause of disease for AD mainly contains following three kinds of sayings: amyloid-beta (β AP) deposition and neurofibrillary tangles (NFT) appear in one on pallium and other brain district nerve.β AP has played vital role in the neurone infringement of AD.Primary cellular defect even death that β AP sedimentation causes in neuron membrane.Its two, the generation of AD has close relationship with old and feeble physiology, the biochemical change that causes.Calcium balance imbalance, free radical increase etc. all can cause neuronic infringement.Its three, AD and central neurotransmitter such as acetylcholine, serotonin, excitatory amino acid etc. are relevant unusually.A large amount of studies confirm that in patient AD, the decline of the forfeiture of learning and memory ability and acetylcholine neural function has direct relation.Cholinergic hypothesis provides theoretical foundation for the treatment of AD, and acetylcholinesterase depressant becomes the most effective means of present treatment AD.
Acetylcholinesterase depressant such as its crin, Physostigmine, lycoremine, neat many piperidines, selagine can strengthen patient's AD cognitive ability, but most medicines have maincenter because of it or the peripheral-system side effect is restricted its widespread use.Therefore the senile dementia disease is required further study and seek a class novel cpd, the acetylcholinesterase depressant that the Development of New Generation toxic side effect is low, curative effect is high.
Summary of the invention
One of purpose of the present invention provide a class new, acetylcholinesterase and butyrylcholine esterase are had the high active pregabalin derivative that suppresses.
The technical scheme that realizes above-mentioned purpose is as follows:
Pregabalin derivative is with shown in the following formula I:
Formula I
Wherein: R is selected from dialkylamine, a nitrogen heterocyclic, diazacyclo, morpholine ring or sulfo-morpholine ring, i.e. R=N[(CH
2)
mCH
3]
2,
Wherein, m is selected from 0～6, x and is selected from 1,2,3,4,5; Y is selected from 0,1,2,3; Z is selected from 0,1,2,3; N is selected from 1～14.
Another object of the present invention provides above-mentioned 4-diethyl amino sylvan derivative and the application in preparation anti-senile dementia disease drug in pharmaceutically acceptable acid or the formed additive salt of alkali.
Another object of the present invention provides a kind of medicine that is used for the treatment of senile dementia.
Concrete technical scheme is as follows:
A kind of pharmaceutical composition of anti-senile dementia disease, its active ingredient are above-mentioned 4-diethyl amino sylvan derivative and at pharmaceutically acceptable acid or the formed additive salt of alkali.
Pregabalin derivative among the present invention is that to be that starting raw material is synthetic by lyrica obtain.
The reaction for preparing pregabalin derivative of the present invention, shown in following reaction formula 1:
The structure of pregabalin derivative is described as follows table 1.
The structure explanation of table 1. pregabalin derivative
Suppress vitro test by acetylcholinesterase and butyrylcholine esterase and show that pregabalin derivative of the present invention has significant anti-acetylcholinesterase and butyrylcholine esterase activity.Compound C 4a wherein, the acetylcholinesterase IC of C4d
50Value is approximate with the contrast lycoremine, and its butyrylcholine esterase IC
50Value is apparently higher than the contrast lycoremine; Simultaneously when n＞3 be n=4,5,6,8 the time, compound has obvious selectivity to the butyrylcholine esterase restraining effect.Therefore 4-diethyl amino sylvan derivative of the present invention can be used for preparing the medicine for the treatment of senile dementia.
Embodiment
The invention will be further described by the following examples.
Embodiment one: 4-(8-bromo octyloxy) phenyl aldehyde (1f) synthetic
With 2.4g (20mmol) p-Hydroxybenzaldehyde, 15ml 1.8-two bromooctanes and 5.52g (40mmol) salt of wormwood (microwave activation) join in the round-bottomed flask of 100ml earlier, add the 40ml anhydrous propanone, stir 24 hours under the reflux conditions.TLC tracks to reaction to complete.Filter, be spin-dried for solvent, obtain head product.The recycle silicon plastic column chromatography separate yellow solid powder 1f, productive rate is 63%.Its
1HNMR (CDCl
3, 300MHz) δ, the ppm data are: 9.86 (s, 1H, CHO), 7.82 (d, J=8.8Hz, 2H, ArH), 6.99 (d, J=8.7Hz, 2H, ArH), 4.04 (t, J=6.5Hz, 2H, H1), 3.20 (t, J=7.0Hz, 2H, H8), 1.88-1.78 (m, 4H, H7, H2), 1.42-1.30 (m, 8H, H3, H4, H5, H6).Determine the structure of product thus.
Prepare 1a, 1b, 1c, 1d, 1e with above-mentioned method.
Embodiment two: BOC protection lyrica is synthetic to n-octyloxy phenyl aldehyde ester (2f)
Get 2mmol 4-(8-bromo octyloxy) phenyl aldehyde (1e) and 20ml dry acetone in the 50ml flask, add 1.2g (5mmol) KI, stir under the room temperature and spend the night.Again with the lyrica of 0.54g (2mmol) BOC protection and the K behind 1g (7.5mmol) microwave activation
2CO
3Add reaction system, be warming up to 60 ℃ and refluxed 24 hours.Post-processing filtering is removed salt of wormwood, removes solvent under reduced pressure, and (developping agent is 1: 9 ethyl acetate to thick product: sherwood oil～1: 2 ethyl acetate: the sherwood oil gradient elution) get BOC protection lyrica to n-octyloxy phenyl aldehyde ester (2f) through silica gel column chromatography.The product structure warp
1The HNMR analytical data is determined.
1H?NMR(CDCl
3，300MHz)δ，ppm：9.86(s，1H，CHO)，7.82(d，J＝8.6Hz，2H，ArH)，6.99(d，J＝8.6Hz，2H，ArH)，3.92(t，J＝6.2Hz，2H，CH
2)，3.72，3.56(s，2H，CH
2)，3.21-3.14(m，1H，CH
2)，3.04-2.97(m，1H，CH
2)，2.27-2.25(m，2H，CH
2)，2.04(br?s，1H，CH)，1.79-1.74(m，2H，CH
2)，1.73-1.65(m，2H，CH
2)，1.45-1.40(m，4H，2CH
2)，1.39(s，9H，3CH
3)，1.38-1.30(m，5H，CH，2CH
2)，1.17-1.12(m，2H，CH
2)，0.88(t，6H，J＝6.2Hz，CH
3)。
Prepare 2a, 2b, 2c, 2d, 2e with above-mentioned method.
Embodiment three: BOC protection lyrica is synthetic to ethoxy benzyl diethylamine ester (3a).
Get 1mmol BOC protection lyrica and align butyl phenyl ether formaldehyde ester (2a), be dissolved in 1 of 20ml drying, in the 2-ethylene dichloride, add 0.1ml (1mmol) secondary amine and stirred 5 minutes.After add the 0.7g sodium triacetoxy borohydride again, stirring is spent the night.After the TLC detection reaction is complete, add the saturated sodium bicarbonate solution termination reaction, ethyl acetate extraction three times.Merge organic relevant dry.(developping agent is 1: 50 methyl alcohol to thick product: methylene dichloride) get yellow oily BOC protection lyrica to n-butoxy benzyl diethylamine ester (3a) through silica gel column chromatography after being spin-dried for solvent.The product structure warp
1The HNMR analytical data is determined.
1H?NMR(CDCl
3，300MHz)δ，ppm：7.22(d，J＝8.6Hz，2H，ArH)，6.84(d，J＝8.6Hz，2H，ArH)，4.42-4.35(m，4H，2CH
2)，3.52(s，2H，CH
2)，3.03-2.99(m，1H，CH
2)，2.94-2.90(m，1H，CH
2)，2.53-2.47(m，4H，NCH
2CH
3)，2.39-2.36(br?s，1H，CH)，2.30-2.28(m，2H，CH
2)，2.18-2.14(m，2H，CH
2)，1.65-1.60(m，1H，CH)，1.39(s，9H，3CH
3)，1.19-1.12(m，2H，CH
2)，1.05(t，6H，J＝7.1Hz，NCH
2CH
3)，0.89(t，6H，J＝6.2Hz，CH
3)。
Prepare 3b, 3c1,3c2,3c3,3c4,3c5,3c6,3d, 3e, 3f with above-mentioned method.
Embodiment four: lyrica is synthetic to n-butoxy benzyl diethylamine ester hydrochloride (4c1).
Protect lyrica that n-butoxy benzyl diethylamine ester (3c1) 0.5mmol is dissolved in methylene dichloride BOC, add 1ml 4NHCl/ methyl alcohol under the ice bath and stir half an hour.Continue under the room temperature to stir to spend the night.Add ether 20ml rotation stirring, product ether repetitive scrubbing 5 times after being spin-dried for solvent.Low temperature is placed in refrigerator at last, can get the yellow oily lyrica to n-butoxy benzyl diethylamine ester hydrochloride (4c1).The product structure warp
1HNMR,
13CNMR, the ESI-MS analytical data is determined.
1H?NMR(CDCl
3，300MHz)δ，ppm：7.22d，J＝8.6Hz，2H，ArH)，6.83(d，J＝8.6Hz，2H，ArH)，4.28(t，J＝6.2Hz，2H，CH
2)，4.03(t，J＝6.2Hz，2H，CH
2)，3.51(s，2H，CH
2)，3.10-3.05(m，1H，CH
2)，3.01-2.98(m，1H，CH
2)，2.54-2.47(m，4H，NCH
2CH
3)，2.38-2.30(br?s，1H，CH)，2.29-2.27(m，2H，CH
2)，2.14-2.09(m，2H，CH
2)，2.08-1.95(m，2H，CH
2)，1.65-1.60(m，1H，CH)，1.19-1.10(m，2H，CH
2)，1.05(t，6H，J＝7.1Hz，NCH
2CH
3)，0.88(t，6H，J＝6.2Hz，CH
3)；
13C?NMR(CDCl
3，75MHz)δ：172.8，160.0，132.8，130.3，115.3，67.5，64.6，55.5，46.2，43.5，41.2，36.9，31.5，28.6，25.5，25.3，22.8，9.2；ESI-MS?m/z：394[M+H]
+.
Prepare 4a, 4b, 4c2,4c3,4c4,4c5,4c6,4d, 4e, 4f with above-mentioned method.
Embodiment five: pregabalin derivative cholinesterase inhibition in-vitro screening
The compounds of this invention, activity test method as anticholinesterase is seen " A New and Rapid Colorimetric Determination of Acetylcholineterase Activity " such as Ellman, Biochem.Pharm.1,88, (1961).
Get the pears type pipe that 5 1.5mL are equipped with 900 μ L 0.1M pH=8.0 phosphate buffered saline buffers respectively, add the certain density sample DMSO solution of 0,5,10,15,20 μ L successively, and add to 920 μ L with DMSO.Add 40 μ L 4mg/mL 5 respectively, 5-dithio two (2-nitrobenzoic acid) and 2 μ L acetylcholinesterase (butyrylcholine esterase) solution, and 37 ℃ of insulations 15 minutes, add 40 μ L 2mg/mL acetylthiocholine (chloro BuCh) solution at once, shake up the back and survey its A value (A at λ=412nm place
n).Reference is with 0.1M pH=8.0 phosphate buffered saline buffer, not add the measured A of sample
ControlValue is as 100 unit of activity:
Relative enzyme activity=(A
n/ A
Control) * 100
With the relative vigor of enzyme inhibitor concentration is mapped then, try to achieve the IC of all cpds according to suppressing curve
50Value (inhibitor concentration during inhibitory enzyme vigor 50%).
The positive contrast of galanthamine hydrobromide.
Test data (the IC of pregabalin derivative acetylcholinesterase and butyrylcholine esterase vitro inhibition activity
50Value) as table 2..Simultaneously, we have also tried to achieve the selectivity of sample to acetylcholinesterase and butyrylcholine esterase inhibition activity, i.e. inhibiting activity of acetylcholinesterase, (IC
50Value) suppresses active (IC with butyrylcholine esterase
50Value) ratio.
Table 2. pregabalin derivative acetylcholinesterase butyrylcholine esterase vitro inhibition activity (IC
50Value)
aAChE，E.C.3.1.1.7，from?electric?eel.
bBChE，E.C.3.1.1.8，from?horse?serum.
cIC
50?values?are?means?of?three?different?experiments.
dIC
50?values?of?AChE?reported?in?the?literature：0.3-0.8μM.
Can draw as drawing a conclusion from table 2.:
(1) it is active that most of pregabalin derivative all has stronger acetylcholinesterase (AChE) inhibition, as the IC of 4c1 and 4c4
50Value (0.98uM, 1.09uM) is in close proximity to the IC of positive reference substance galanthamine hydrobromide
50Value (0.67uM).
(2) pregabalin derivative that is synthesized will be apparently higher than positive reference substance galanthamine hydrobromide, especially 4c1, its IC to the inhibition activity of butyrylcholine esterase (BuChE)
50Value reaches 51nM.
(3) pregabalin derivative that is synthesized has very high selectivity to butyrylcholine esterase, namely to acetylcholinesterase IC
50The value with to BuCh ester IC
50The ratio of value is bigger.The selective value of positive reference substance galanthamine hydrobromide be the selective value of 0.44,4c1 and 4c2 up to 19.21 and 18.35, be respectively 43.7 times and 41.7 times of reference substance.
Claims (7)
1. the aminomethyl of the 3-shown in the formula I-5-methylhexanoic acid derivative and at pharmaceutically acceptable acid or the formed additive salt of alkali:
Formula I
R=N ［ (CH
2)
mCH
3 2,
Wherein, m is selected from 0～6, x and is selected from 1,2,3,4,5; Y is selected from 0,1,2,3; Z is selected from 0,1,2,3; N is selected from 1～15.
2. 3-aminomethyl according to claim 1-5-methylhexanoic acid derivative and at pharmaceutically acceptable acid or the formed additive salt of alkali, it is characterized in that: described m is selected from 0～5, x and is selected from 1,2,3,4; Y is selected from 0,1,2; Z is selected from 0,1,2; N is selected from 2～13.
3. 3-aminomethyl according to claim 2-5-methylhexanoic acid derivative and at pharmaceutically acceptable acid or the formed additive salt of alkali, it is characterized in that: described m is selected from 0～4, x and is selected from 1,2,3; Y is selected from 0,1, z is selected from 1,2; N is selected from 4～12.
4. 3-aminomethyl according to claim 3-5-methylhexanoic acid derivative and at pharmaceutically acceptable acid or the formed additive salt of alkali is characterized in that: R=N ［ (CH
2)
mCH
3 2,
Wherein, m is selected from 1,2,3; N is selected from 4～8.
5. 3-aminomethyl according to claim 1-5-methylhexanoic acid derivative and at pharmaceutically acceptable acid or the formed additive salt of alkali is characterized in that it is selected from following compounds:
Lyrica is to ethoxy benzyl diethylamine ester hydrochloride;
Lyrica is to positive propoxy benzyl diethylamine ester hydrochloride;
Lyrica is to n-butoxy benzyl diethylamine ester hydrochloride;
Lyrica is to the positive dipropyl amine ester hydrochloride of n-butoxy benzyl;
Lyrica is to the positive dibutylamine ester hydrochloride of n-butoxy benzyl;
Lyrica is to n-butoxy benzyl-pyrrole alkane ester hydrochloride;
Lyrica is to n-butoxy benzyl piepridine ester hydrochloride;
Lyrica is to n-butoxy benzyl morphine quinoline ester hydrochloride;
Lyrica is to n-pentyloxy benzyl diethylamine ester hydrochloride;
Lyrica aligns hexyloxy benzyl diethylamine ester hydrochloride;
Lyrica is to n-octyloxy benzyl diethylamine ester hydrochloride.
6. the pharmaceutical composition of an anti-senile dementia disease is characterized in that, its active ingredient is the arbitrary described 3-aminomethyl of claim 1-5-5-methylhexanoic acid derivative and at pharmaceutically acceptable acid or the formed additive salt of alkali.
7. the arbitrary described 3-aminomethyl of claim 1-5-5-methylhexanoic acid derivative and the application in preparation anti-senile dementia disease drug in pharmaceutically acceptable acid or the formed additive salt of alkali thereof.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5563175A (en) * | 1990-11-27 | 1996-10-08 | Northwestern University | GABA and L-glutamic acid analogs for antiseizure treatment |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2374755C (en) * | 1999-06-10 | 2010-03-30 | Warner-Lambert Company | Mono- and disubstituted 3-propyl gamma-aminobutyric acids |
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2010
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5563175A (en) * | 1990-11-27 | 1996-10-08 | Northwestern University | GABA and L-glutamic acid analogs for antiseizure treatment |
Non-Patent Citations (9)
| Title |
|---|
| #352 * |
| Š |
| & * |
| Daniel M.ect.Pregabalin: A novel γ-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders.《Clinical Therapeutics》.2007,第29卷(第1期),26-48. |
| MEDICINAL CHEMISTRY LETTERS 》.2010,第20卷(第15期),4683-4688. * |
| Myatt, JW ，ect.Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain.《 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 》.2010,第20卷(第15期),4683-4688. |
| Myatt, JW,ect.Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain.《 BIOORGANIC & * |
| Pregabalin: A novel γ-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders;Daniel M.ect;《Clinical Therapeutics》;20070131;第29卷(第1期);26-28 * |
| tefica Horvat, ect.Synthesis, characterization and in vitro pharmacology of novel pregabalin derivatives.《European Journal of Medicinal Chemistry》.2010,第45卷(第4期),1447-1452. * |
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