CN102887910B - 7-alkoxyl-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one derivant as antuepileptic and preparation method thereof - Google Patents
7-alkoxyl-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one derivant as antuepileptic and preparation method thereof Download PDFInfo
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- CN102887910B CN102887910B CN201210316306.9A CN201210316306A CN102887910B CN 102887910 B CN102887910 B CN 102887910B CN 201210316306 A CN201210316306 A CN 201210316306A CN 102887910 B CN102887910 B CN 102887910B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 241001597008 Nomeidae Species 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000001961 anticonvulsive agent Substances 0.000 claims description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 6
- 230000003556 anti-epileptic effect Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
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- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical group C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 abstract 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 abstract 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides 7 alkoxyls [1,2,4] triazol [3,4 b] benzothiazole 3 (2H) ketonic compound (I) that a class is new, and preparation method thereof.Also relate to this compounds for preparing the purposes of antuepileptic.
Description
Technical field
The present invention relates to the preparation of 7-alkoxyl-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one derivant
Method and its purposes in preparing antiepileptic.
Background technology
Epilepsy is the collective term for describing one group of chronic convulsive disorders, and the common trait of these symptoms is to occur temporarily
Property epilepsy is also attended by loss of consciousness or obstacle.Epilepsy is only second to the second largest disease of cerebrovascular disease as Neurology Department
Disease, not only makes patient's body and mind come to harm, and has a strong impact on study, work and daily life, even results in unexpected death, is
The common disease of serious threat people's life and health.
Adding up according to WHO, whole world epileptic there are about 50,000,000 people at present, and wherein 80% in developing country, the most also goes out
Existing 2,000,000 new epileptics.Country variant epilepsy invasion rate is different, the most about 5-10 ‰, and the epilepsy prevalence of China is 7 ‰,
Close with the sickness rate of the developing country 7.2 ‰ of WHO report.At present China's epileptic's number has reached 10,000,000 more than, and
There is the neopathy people of nearly 400,000 every year.The Main Means controlling epilepsy at present is Drug therapy, and the purpose of its treatment exists
In reducing or preventing epilepsy.In clinical practice, existing multiple antuepileptic is available, such as phenobarbital, phenytoin, card
Horse Xiping, valproic acid, lamotrigine, non-urethane, topiramate etc., although these medicines can protect patient to varying degrees
There is not various epileptic convulsion, but it exists side effect and feeling bad property, thus prevent and use them in long-term treatment.For
Improvement therapeutic effect and elimination or reduce side reaction, need to have new architectural feature and the novel compounds of the new mechanism of action
Thing.
Summary of the invention
For solving as above problem, the invention provides the novel 7-alkoxyl of a class-[1,2,4] triazol [3,4-b] benzene
And thiazole-3 (2H)-one compound, with and preparation method thereof.This compounds has the spy that anti-convulsant activity is strong and toxicity is little
Levy, can be used for preparing antiepileptic.
The present invention provides the compound represented by formula I
Wherein, R is n-pro-pyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, dodecyl, benzyl, 2-
Luorobenzyl, 3-luorobenzyl, 4-luorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-methyl
Benzyl, 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl.
The present invention also provides for more than one and states invention compound is active component, contains one or more simultaneously and pharmaceutically may be used
With the carrier accepted or the pharmaceutical composition of adjuvant.
Indication of the present invention pharmaceutically acceptable carrier or adjuvant, be selected from pharmaceutical preparation conventional excipient, auxiliary
Material or solvent.Such as lactose, sucrose, dextrin, Pulvis Talci, gelatin, agar, pectin, Radix Acaciae senegalis, magnesium stearate, stearic acid, fibre
The lower alkyl ether corn starch of dimension element, potato starch, natural gum, syrup, Oleum Arachidis hypogaeae semen, olive oil, phospholipid, single stearic fat acid are sweet
Grease, distearyl glycerol, fatty acid, fatty acid amine, coloring agent, preservative, correctives, water, ethanol, propanol, physiology
Saline, glucose solution etc..
By the method for thing shown in formula I in the preparation present invention, the method is with II as initial substance:
Compound (II) and carbamide carry out ring-closure reaction, obtain the compound shown in formula I.
Such compou nd synthesis method is simple, and rationally, production cost is low.
The compound represented by formula I and its pharmaceutical composition may be used for the preparation of antiepileptic.
The compounds of this invention has anti-convulsant activity, so that they can be used as antiepileptic.Excellent in the present invention
Select compound 7-butoxy-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one (compound Id) pharmacological evaluation
The results are shown in Table 1.During oral administration, the median effective dose of compound Id is 34.1mg/kg, and half toxic dose is 1710.4mg/
Kg, protective index PI i.e. neurotoxicity is up to 50.2 with the ratio of effective dose.And compare medicine carbamazepine when oral administration
Half toxic dose be 204.4mg/kg, protective index is 11.1.Compound Id is low compared with carbamazepine neurotoxicity 9 times
(1710.4/204.4), protective index is more than 4 times of carbamazepine.The maximum untoward reaction of the antuepileptic of existing clinical practice is just
It is to neural toxic reaction.During so now developing new antuepileptic, neurotoxicity has been extremely important evaluation
Index.The maximum advantage of the compound of the present invention is that neurotoxicity is the lowest, and protective index is apparently higher than clinical medicine Karma west
Flat.
Detailed description of the invention
Below by way of preferred compound Id synthesis example and pharmacological evaluation example embodiment to the present invention above-mentioned in
Appearance is described in further detail, but this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to following example.
Preparation example 1:
With introductionization as a example by 7-butoxy-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one (compound Id)
Method is led in the synthesis of compound I
It is heated to melting by compound II (10mmol) and carbamide (80mmol).TLC follows the tracks of reaction, will be anti-after reaction completely
Answering thing to pour 0.5 hour sucking filtration of stirring in hot water into and obtain crude product, column chromatography for separation (dichloromethane: methanol, 50: 1) is changed
Compound Id.Fusing point 162-164 DEG C, yield 63.5%；1H NMR (300MHz, CDCl3): δ 10.15 (s, 1H ,-NH), 7.89 (d, J
=8.8Hz, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 6.95 (d, J=8.8Hz, 1H, Ar-H), 3.99 (t, J=6.3Hz,
2H ,-OCH2-), 1.90-1.67 (m, 2H ,-CH2-), 1.62-1.39 (m, 2H ,-CH2-), 0.99 (t, J=7.2Hz, 3H ,-
CH3) .IR (KBr, cm-1): 3152 (N-H), 1697 (C=O) .MS m/z 264 (M+1) .Anal.Calcd.for
C12H13N3O2S:C, 54.74；H, 4.98；N, 15.96.Found:C, 54.83；H, 4.79；N, 16.01.
Embodiment A: convulsion pharmacological evaluation and neurotoxicity experiment
With introductionization as a example by 7-butoxy-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one (compound Id)
The pharmacological experimental method of compound I
Maximal electrical seizure (MES) is used to evaluate the anti-convulsant activity of compound.Take 9 kunming mices (male and female regardless of)
Being divided into 3 groups, often group 3, respectively oral administration 30mg/kg, the compound Id of 100mg/kg, 300mg/kg dosage, after 0.5 hour
Test mice is carried out 60 hertz, 110 volts, the single electricity irritation of 0.3 second, observe the compound guarantor to electricity irritation induced convulsions
Protect situation.It is set to effectively so that hind leg is the most tetanic.For a hundred per cent compounds effective under 100mg/kg dosage, by improvement Kou Shi
Method evaluates its median effective dose further.The median effective dose recording compound Id is 34.08mg/kg.Mice rotating rod moves
Mice after oral administration 0.5 hour, in order to evaluate the neurotoxicity of compound, is placed on the thick of diameter 1 inch by imbalance test
On rough rotating rod, rotating with the speed of 6 turns per minute, mice is able to maintain that balance 1 minute does not fall down and thinks not
There is neurotoxicity, otherwise then have neurotoxicity.Evaluate its half neurotoxicity further by improvement karber's method equally, and then calculate
Go out protective index PI value (being shown in Table 1).Convulsion pharmacological evaluation and neurotoxicity experiment refer to document Krall, R.J.；Penry,
J.K.；White, B.G.；Kupferberg, H.J.；Swinyard, E.A.Epilepsia.1978,19,409.
Table 1: compound Id convulsion pharmacological evaluation and neurotoxicity experimental result (mg/kg, oral)
Above-described is only the several embodiments of the present invention, can not therefore be interpreted as the scope of the claims of the present invention
Restriction, it is noted that for member of ordinary skill in the art, without departing from the inventive concept of the premise, it is also possible to
Making some other deformation and improvement, these broadly fall into protection scope of the present invention.
Claims (4)
1. the compound shown in formula (I):
Wherein, R is normal-butyl.
2. a pharmaceutical composition, it is characterised in that it contains with the compound described in claim 1 as active component simultaneously
Kind or multiple pharmaceutically acceptable carrier mass and/or adjuvant.
3. according to the compound described in claim 1 and 2 or pharmaceutical composition in the application prepared on antiepileptic.
The preparation method of compound the most according to claim 1, is characterized in that using compound II and carbamide ring-closure reaction
Wherein, R is normal-butyl.
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| CN201210316306.9A CN102887910B (en) | 2012-08-27 | 2012-08-27 | 7-alkoxyl-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one derivant as antuepileptic and preparation method thereof |
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| CN201210316306.9A CN102887910B (en) | 2012-08-27 | 2012-08-27 | 7-alkoxyl-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one derivant as antuepileptic and preparation method thereof |
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| Publication Number | Publication Date |
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| CN102887910A CN102887910A (en) | 2013-01-23 |
| CN102887910B true CN102887910B (en) | 2016-08-24 |
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| CN201210316306.9A Expired - Fee Related CN102887910B (en) | 2012-08-27 | 2012-08-27 | 7-alkoxyl-[1,2,4] triazol [3,4-b] benzothiazole-3 (2H)-one derivant as antuepileptic and preparation method thereof |
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| US3859297A (en) * | 1969-11-28 | 1975-01-07 | Monsanto Co | Method for preparation of organic azolyl polysulfides |
| CN1807419A (en) * | 2006-01-26 | 2006-07-26 | 全哲山 | 1,2,4-triazole [4,3-alpha] chinoline -1-one derivative as antiepileptics medicine and its pharmaceutical salts |
| CN101676287A (en) * | 2008-09-19 | 2010-03-24 | 全哲山 | 6-(substituted phenoxy)-tetrazolo[5,1-a] phthalazine derivatives as antuepileptics and their pharmaceutically acceptable salts |
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2012
- 2012-08-27 CN CN201210316306.9A patent/CN102887910B/en not_active Expired - Fee Related
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| US3859297A (en) * | 1969-11-28 | 1975-01-07 | Monsanto Co | Method for preparation of organic azolyl polysulfides |
| CN1807419A (en) * | 2006-01-26 | 2006-07-26 | 全哲山 | 1,2,4-triazole [4,3-alpha] chinoline -1-one derivative as antiepileptics medicine and its pharmaceutical salts |
| CN101676287A (en) * | 2008-09-19 | 2010-03-24 | 全哲山 | 6-(substituted phenoxy)-tetrazolo[5,1-a] phthalazine derivatives as antuepileptics and their pharmaceutically acceptable salts |
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| 1,2,4-三唑并[4,3-a]喹啉衍生物的合成及其抗惊厥活性;李元春，等;《中国药物化学杂志》;20110228;第21卷(第1期);12-18 * |
| Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones;Hong-Guang Jin,等;《Bioorganic & Medicinal Chemistry》;20060714;第14卷(第20期);6868-6873 * |
| Synthesis and anticonvulsant activities of some triazolothiadiazole derivatives;Xian-Qing Deng,等;《Archiv der Pharmazie》;20120425;第345卷(第7期);565-573 * |
| Synthesis and Anticonvulsant Activity of 1-Substituted-7-Benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline.;Li-Jing Cui,等;《Biol. Pharm. Bull.》;20051231;第28卷(第7期);1216-1220 * |
| Synthesis and Anticonvulsant Activity of 7-Alkoxy-Triazolo-[3,4-b]Benzo[d]Thiazoles;Xian-Qing Deng, 等;《Medicinal Chemistry》;20101231;第6卷(第5期);313-320 * |
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| CN102887910A (en) | 2013-01-23 |
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